Heterocyclic derivatives as modulators of ion channels

ABSTRACT

The present invention relates to heterocyclic derivatives useful as inhibitors of ion channels. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit under 35 U.S.C. § 119 to U.S.provisional patent application Ser. No. 60/987,490, filed Nov. 13, 2007,the contents of which are incorporated herein by reference.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to compounds useful as inhibitors of ionchannels. The invention also provides pharmaceutically acceptablecompositions comprising the compounds of the invention and methods ofusing the compositions in the treatment of various disorders.

BACKGROUND OF THE INVENTION

Na channels are central to the generation of action potentials in allexcitable cells such as neurons and myocytes. They play key roles inexcitable tissue including brain, smooth muscles of the gastrointestinaltract, skeletal muscle, the peripheral nervous system, spinal cord andairway. As such they play key roles in a variety of disease states suchas epilepsy (See, Moulard, B. and D. Bertrand (2002) “Epilepsy andsodium channel blockers” Expert Opin. Ther. Patents 12(1): 85-91)), pain(See, Waxman, S. G., S. Dib-Hajj, et al. (1999) “Sodium channels andpain” Proc Natl Acad Sci USA 96(14): 7635-9 and Waxman, S. G., T. R.Cummins, et al. (2000) “Voltage-gated sodium channels and the molecularpathogenesis of pain: a review” J Rehabil Res Dev 37(5): 517-28),myotonia (See Meola, G. and V. Sansone (2000) “Therapy in myotonicdisorders and in muscle channelopathies” Neurol Sci 21(5): S953-61 andMankodi, A. and C. A. Thornton (2002) “Myotonic syndromes” Curr OpinNeurol 15(5): 545-52), ataxia (See, Meisler, M. H., J. A. Kearney, etal. (2002) “Mutations of voltage-gated sodium channels in movementdisorders and epilepsy” Novartis Found Symp 241: 72-81), multiplesclerosis (See, Black, J. A., S. Dib-Hajj, et al. (2000) “Sensoryneuron-specific sodium channel SNS is abnormally expressed in the brainsof mice with experimental allergic encephalomyelitis and humans withmultiple sclerosis” Proc Natl Acad Sci USA 97(21): 11598-602, andRenganathan, M., M. Gelderblom, et al. (2003) “Expression of Na(v)1.8sodium channels perturbs the firing patterns of cerebellar purkinjecells” Brain Res 959(2): 235-42), irritable bowel (See Su, X., R. E.Wachtel, et al. (1999) “Capsaicin sensitivity and voltage-gated sodiumcurrents in colon sensory neurons from rat dorsal root ganglia” Am JPhysiol 277(6 Pt 1): G1180-8, and Laird, J. M., V. Souslova, et al.(2002) “Deficits in visceral pain and referred hyperalgesia in Nav1.8(SNS/PN3)-null mice” J Neurosci 22(19): 8352-6), urinary incontinenceand visceral pain (See, Yoshimura, N., S. Seki, et al. (2001) “Theinvolvement of the tetrodotoxin-resistant sodium channel Na(v) 1.8(PN3/SNS) in a rat model of visceral pain” J Neurosci 21(21): 8690-6),as well as an array of psychiatry dysfunctions such as anxiety anddepression (See, Hurley, S. C. (2002) “Lamotrigine update and its use inmood disorders” Ann Pharmacother 36(5): 860-73).

Voltage gated Na channels comprise a gene family consisting of 9different subtypes (NaV1.1-NaV1.9). As shown in Table 1, these subtypesshow tissue specific localization and functional differences (See,Goldin, A. L. (2001) “Resurgence of sodium channel research” Annu RevPhysiol 63: 871-94). Three members of the gene family (NaV1.8, 1.9, 1.5)are resistant to block by the well-known Na channel blocker TTX,demonstrating subtype specificity within this gene family. Mutationalanalysis has identified glutamate 387 as a critical residue for TTXbinding (See Noda, M., H. Suzuki, et al. (1989) “A single point mutationconfers tetrodotoxin and saxitoxin insensitivity on the sodium channelII” FEBS Lett 259(1): 213-6).

TABLE 1 Na isoform Tissue TTX IC50 Indications NaV1.1 CNS, PNS 10 nMPain, Epilepsy, soma of neurodegeneration neurons NaV1.2 CNS, high in 10nM Neurodegeneration axons Epilepsy NaV1.3 CNS, 15 nM Pain embryonic,injured nerves NaV1.4 Skeletal 25 nM Myotonia muscle NaV1.5 Heart  2 μMArrhythmia, long QT NaV1.6 CNS  6 nM Pain, movement disorderswidespread, most abundant NaV1.7 PNS, DRG, 25 nM Pain, Neuroendocrineterminals disorders neuroendocrine NaV1.8 PNS, small >50 μM  Painneurons in DRG &TG NaV1.9 PNS, small  1 μM Pain neurons in DRG &TG(Abbreviations: CNS = central nervous system, PNS = peripheral nervoussytem, DRG = dorsal root ganglion, TG = Trigeminal ganglion):

In general, voltage-gated sodium channels (NaVs) are responsible forinitiating the rapid upstroke of action potentials in excitable tissuein nervous system, which transmit the electrical signals that composeand encode normal and aberrant pain sensations. Antagonists of NaVchannels can attenuate these pain signals and are useful for treating avariety of pain conditions, including but not limited to acute, chronic,inflammatory, and neuropathic pain. Known NaV antagonists, such as TTX,lidocaine (See, Mao, J. and L. L. Chen (2000) “Systemic lidocaine forneuropathic pain relief” Pain 87(1): 7-17.) bupivacaine, phenyloin (See,Jensen, T. S. (2002) “Anticonvulsants in neuropathic pain: rationale andclinical evidence” Eur J Pain 6 (Suppl A): 61-8), lamotrigine (See,Rozen, T. D. (2001) “Antiepileptic drugs in the management of clusterheadache and trigeminal neuralgia” Headache 41 Suppl 1: S25-32 andJensen, T. S. (2002) “Anticonvulsants in neuropathic pain: rationale andclinical evidence” Eur J Pain 6 (Suppl A): 61-8.), and carbamazepine(See, Backonja, M. M. (2002) “Use of anticonvulsants for treatment ofneuropathic pain” Neurology 59(5 Suppl 2): S14-7), have been shown to beuseful attenuating pain in humans and animal models.

Hyperalgesia (extreme sensitivity to something painful) that develops inthe presence of tissue injury or inflammation reflects, at least inpart, an increase in the excitability of high-threshold primary afferentneurons innervating the site of injury. Voltage sensitive sodiumchannels activation is critical for the generation and propagation ofneuronal action potentials. There is a growing body of evidenceindicating that modulation of NaV currents is an endogenous mechanismused to control neuronal excitability (See, Goldin, A. L. (2001)“Resurgence of sodium channel research” Annu Rev Physiol 63: 871-94).Several kinetically and pharmacologically distinct voltage-gated sodiumchannels are found in dorsal root ganglion (DRG) neurons. TheTTX-resistant current is insensitive to micromolar concentrations oftetrodotoxin, and displays slow activation and inactivation kinetics anda more depolarized activation threshold when compared to othervoltage-gated sodium channels. TTX-resistant sodium currents areprimarily restricted to a subpopulation of sensory neurons likely to beinvolved in nociception. Specifically, TTX-resistant sodium currents areexpressed almost exclusively in neurons that have a small cell-bodydiameter; and give rise to small-diameter slow-conducting axons and thatare responsive to capsaicin. A large body of experimental evidencedemonstrates that TTX-resistant sodium channels are expressed onC-fibers and are important in the transmission of nociceptiveinformation to the spinal cord.

Intrathecal administration of antisense oligo-deoxynucleotides targetinga unique region of the TTX-resistant sodium channel (NaV1.8) resulted ina significant reduction in PGE₂-induced hyperalgesia (See, Khasar, S.G., M. S. Gold, et al. (1998) “A tetrodotoxin-resistant sodium currentmediates inflammatory pain in the rat” Neurosci Lett 256(1): 17-20).More recently, a knockout mouse line was generated by Wood andcolleagues, which lacks functional NaV1.8. The mutation has an analgesiceffect in tests assessing the animal's response to the inflammatoryagent carrageenan (See, Akopian, A. N., V. Souslova, et al. (1999) “Thetetrodotoxin-resistant sodium channel SNS has a specialized function inpain pathways” Nat Neurosci 2(6): 541-8.). In addition, deficit in bothmechano- and thermoreception were observed in these animals. Theanalgesia shown by the Nav1.8 knockout mutants is consistent withobservations about the role of TTX-resistant currents in nociception.

Immunohistochemical, in-situ hybridization and in-vitroelectrophysiology experiments have all shown that the sodium channelNaV1.8 is selectively localized to the small sensory neurons of thedorsal root ganglion and trigeminal ganglion (See, Akopian, A. N., L.Sivilotti, et al. (1996) “A tetrodotoxin-resistant voltage-gated sodiumchannel expressed by sensory neurons” Nature 379(6562): 257-62.). Theprimary role of these neurons is the detection and transmission ofnociceptive stimuli. Antisense and immunohistochemical evidence alsosupports a role for NaV1.8 in neuropathic pain (See, Lai, J., M. S.Gold, et al. (2002) “Inhibition of neuropathic pain by decreasedexpression of the tetrodotoxin-resistant sodium channel, NaV1.8” Pain95(1-2): 143-52, and Lai, J., J. C. Hunter, et al. (2000) “Blockade ofneuropathic pain by antisense targeting of tetrodotoxin-resistant sodiumchannels in sensory neurons” Methods Enzymol 314: 201-13.). NaV1.8protein is upregulated along uninjured C-fibers adjacent to the nerveinjury. Antisense treatment prevents the redistribution of NaV1.8 alongthe nerve and reverses neuropathic pain. Taken together thegene-knockout and antisense data support a role for NaV1.8 in thedetection and transmission of inflammatory and neuropathic pain.

In neuropathic pain states there is a remodeling of Na channeldistribution and subtype. In the injured nerve, expression of NaV1.8 andNaV1.9 are greatly reduced whereas expression of the TTX sensitivesubunit NaV1.3 is 5-10 fold upregulated (See, Dib-Hajj, S. D., J. Fjell,et al. (1999) “Plasticity of sodium channel expression in DRG neurons inthe chronic constriction injury model of neuropathic pain.” Pain 83(3):591-600.) The timecourse of the increase in NaV1.3 parallels theappearance of allodynia in animal models subsequent to nerve injury. Thebiophysics of the NaV1.3 channel is distinctive in that it shows veryfast repriming after inactivation following an action potential. Thisallows for sustained rates of high firing as is often seen in theinjured nerve (See, Cummins, T. R., F. Aglieco, et al. (2001) “Nav1.3sodium channels: rapid repriming and slow closed-state inactivationdisplay quantitative differences after expression in a mammalian cellline and in spinal sensory neurons” J Neurosci 21(16): 5952-61.). NaV1.3is expressed in the central and peripheral systems of man. NaV1.9 issimilar to NaV1.8 as it is selectively localized to small sensoryneurons of the dorsal root ganglion and trigeminal ganglion (See, Fang,X., L. Djouhri, et al. (2002). “The presence and role of thetetrodotoxin-resistant sodium channel Na(v)1.9 (NaN) in nociceptiveprimary afferent neurons.” J Neurosci 22(17): 7425-33.). It has a slowrate of inactivation and left-shifted voltage dependence for activation(See, Dib-Hajj, S., J. A. Black, et al. (2002) “NaN/Nav1.9: a sodiumchannel with unique properties” Trends Neurosci 25(5): 253-9.). Thesetwo biophysical properties allow NaV1.9 to play a role in establishingthe resting membrane potential of nociceptive neurons. The restingmembrane potential of NaV1.9 expressing cells is in the −55 to −50 mVrange compared to −65 mV for most other peripheral and central neurons.This persistent depolarization is in large part due to the sustainedlow-level activation of NaV1.9 channels. This depolarization allows theneurons to more easily reach the threshold for firing action potentialsin response to nociceptive stimuli. Compounds that block the NaV1.9channel may play an important role in establishing the set point fordetection of painful stimuli. In chronic pain states, nerve and nerveending can become swollen and hypersensitive exhibiting high frequencyaction potential firing with mild or even no stimulation. Thesepathologic nerve swellings are termed neuromas and the primary Nachannels expressed in them are NaV1.8 and NaV1.7 (See Kretschmer, T., L.T. Happel, et al. (2002) “Accumulation of PN1 and PN3 sodium channels inpainful human neuroma-evidence from immunocytochemistry” Acta Neurochir(Wien) 144(8): 803-10; discussion 810.). NaV1.6 and NaV1.7 are alsoexpressed in dorsal root ganglion neurons and contribute to the smallTTX sensitive component seen in these cells. NaV1.7 in particular maytherefore be a potential pain target in addition to it's role inneuroendocrine excitability (See, Klugbauer, N., L. Lacinova, et al.(1995) “Structure and functional expression of a new member of thetetrodotoxin-sensitive voltage-activated sodium channel family fromhuman neuroendocrine cells” Embo J 14(6): 1084-90).

NaV1.1 (See Sugawara, T., E. Mazaki-Miyazaki, et al. (2001) “Nav1.1mutations cause febrile seizures associated with afebrile partialseizures.” Neurology 57(4): 703-5.) and NaV1.2 (See Sugawara, T., Y.Tsurubuchi, et al. (2001) “A missense mutation of the Na+ channel alphaII subunit gene Na(v) 1.2 in a patient with febrile and afebrileseizures causes channel dysfunction” Proc Natl Acad Sci USA 98(11):6384-9) have been linked to epilepsy conditions including febrileseizures. There are over 9 genetic mutations in NaV1.1 associated withfebrile seizures (See, Meisler, M. H., J. A. Kearney, et al. (2002)“Mutations of voltage-gated sodium channels in movement disorders andepilepsy” Novartis Found Symp 241: 72-81)

Antagonists for NaV1.5 have been developed and used to treat cardiacarrhythmias. A gene defect in NaV1.5 that produces a largernoninactivating component to the current has been linked to long QT inman and the orally available local anesthetic mexilitine has been usedto treat this condition (See Wang, D. W., K. Yazawa, et al. (1997)“Pharmacological targeting of long QT mutant sodium channels.” J ClinInvest 99(7): 1714-20).

Several Na channel blockers are currently used or being tested in theclinic to treat epilepsy (See, Moulard, B. and D. Bertrand (2002)“Epilepsy and sodium channel blockers” Expert Opin. Ther. Patents 12(1):85-91.); acute (See, Wiffen, P., S. Collins, et al. (2000)“Anticonvulsant drugs for acute and chronic pain” Cochrane Database SystRev 3), chronic (See, Wiffen, P., S. Collins, et al. (2000)“Anticonvulsant drugs for acute and chronic pain” Cochrane Database SystRev 3, and Guay, D. R. (2001) “Adjunctive agents in the management ofchronic pain” Pharmacotherapy 21(9): 1070-81), inflammatory (See, Gold,M. S. (1999) “Tetrodotoxin-resistant Na+ currents and inflammatoryhyperalgesia.” Proc Natl Acad Sci USA 96(14): 7645-9), and neuropathicpain (See Strichartz, G. R., Z. Zhou, et al. (2002) “Therapeuticconcentrations of local anaesthetics unveil the potential role of sodiumchannels in neuropathic pain” Novartis Found Symp 241: 189-201, andSandner-Kiesling, A., G. Rumpold Seitlinger, et al. (2002) “Lamotriginemonotherapy for control of neuralgia after nerve section” ActaAnaesthesiol Scand 46(10): 1261-4); cardiac arrhythmias (See, An, R. H.,R. Bangalore, et al. (1996) “Lidocaine block of LQT-3 mutant human Na+channels” Circ Res 79(1): 103-8, and Wang, D. W., K. Yazawa, et al.(1997) “Pharmacological targeting of long QT mutant sodium channels” JClin Invest 99(7): 1714-20); neuroprotection (See, Taylor, C. P. and L.S. Narasimhan (1997) “Sodium channels and therapy of central nervoussystem diseases” Adv Pharmacol 39: 47-98) and as anesthetics (SeeStrichartz, G. R., Z. Zhou, et al. (2002) “Therapeutic concentrations oflocal anaesthetics unveil the potential role of sodium channels inneuropathic pain” Novartis Found Symp 241: 189-201).

Various animal models with clinical significance have been developed forthe study of sodium channel modulators for numerous different painindications. E.g., malignant chronic pain, see, Kohase, H., et al., ActaAnaesthesiol Scand. 2004; 48(3):382-3; femur cancer pain (see, Kohase,H., et al., Acta Anaesthesiol Scand. 2004; 48(3):382-3); non-malignantchronic bone pain (see, Ciocon, J. O. et al., J Am Geriatr Soc. 1994;42(6):593-6); rheumatoid arthritis (see, Calvino, B. et al., Behav BrainRes. 1987; 24(1):11-29); osteoarthritis (see, Guzman, R. E., et al.,Toxicol Pathol. 2003; 31(6):619-24); spinal stenosis (see, Takenobu, Y.et al., J Neurosci Methods. 2001; 104(2):191-8); Neuropathic low backpain (see, Hines, R., et al., Pain Med. 2002; 3(4):361-5; Massie, J. B.,et al., J Neurosci Methods. 2004; 137(2):283-9; neuropathic low backpain (see, Hines, R., et al., Pain Med. 2002; 3(4):361-5; Massie, J. B.,et al., J Neurosci Methods. 2004; 137(2):283-9); myofascial painsyndrome (see, Dalpiaz & Dodds, J Pain Palliat Care Pharmacother. 2002;16(1):99-104; Sluka K A et al., Muscle Nerve. 2001; 24(1):37-46);fibromyalgia (see, Bennet & Tai, Int J Clin Pharmacol Res. 1995;15(3):115-9); temporomandibular joint pain (see, Ime H, Ren K, Brain ResMol Brain Res. 1999; 67(1):87-97); chronic visceral pain, including,abdominal (see, Al-Chaer, E. D., et al., Gastroenterology. 2000;119(5):1276-85); pelvic/perineal pain, (see, Wesselmann et al., NeurosciLett. 1998; 246(2):73-6); pancreatic (see, Vera-Portocarrero, L. B., etal., Anesthesiology. 2003; 98(2):474-84); IBS pain (see, Verne, G. N.,et al., Pain. 2003; 105(1-2):223-30; La J H et al., World Gastroenterol.2003; 9(12):2791-5); chronic headache pain (see, Willimas & Stark,Cephalalgia. 2003; 23(10):963-71); migraine (see, Yamamura, H., et al.,J Neurophysiol. 1999; 81(2):479-93); tension headache, including,cluster headaches (see, Costa, A., et al., Cephalalgia. 2000;20(2):85-91); chronic neuropathic pain, including, post-herpeticneuralgia (see, Attal, N., et al., Neurology. 2004; 62(2):218-25; Kim &Chung 1992, Pain 50:355); diabetic neuropathy (see, Beidoun A et al.,Clin J Pain. 2004; 20(3):174-8; Courteix, C., et al., Pain. 1993;53(1):81-8); HIV-associated neuropathy (see, Portegies & Rosenberg, NedTijdschr Geneeskd. 2001; 145(15):731-5; Joseph E K et al., Pain. 2004;107(1-2):147-58; Oh, S. B., et al., J. Neurosci. 2001; 21(14):5027-35);trigeminal neuralgia (see, Sato, J., et al., Oral Surg Oral Med OralPathol Oral Radiol Endod. 2004; 97(1):18-22; Imamura Y et al., Exp BrainRes. 1997; 116(1):97-103); Charcot-Marie Tooth neuropathy (see, Sereda,M., et al., Neuron. 1996; 16(5):1049-60); hereditary sensoryneuropathies (see, Lee, M. J., et al., Hum Mol. Genet. 2003;12(15):1917-25); peripheral nerve injury (see, Attal, N., et al.,Neurology. 2004; 62(2):218-25; Kim & Chung 1992, Pain 50:355; Bennett &Xie, 1988, Pain 33:87; Decostered, I. & Woolf, C. J., 2000, Pain 87:149;Shir, Y. & Seltzer, Z. 1990; Neurosci Lett 115:62); painful neuromas(see, Nahabedian & Johnson, Ann Plast Surg. 2001; 46(1):15-22; Devor &Raber, Behav Neural Biol. 1983; 37(2):276-83); ectopic proximal anddistal discharges (see, Liu, X. et al., Brain Res. 2001; 900(1):119-27);radiculopathy (see, Devers & Galer, (see, Clin J Pain. 2000;16(3):205-8; Hayashi N et al., Spine. 1998; 23(8):877-85); chemotherapyinduced neuropathic pain (see, Aley, K. O., et al., Neuroscience. 1996;73(1):259-65); radiotherapy-induced neuropathic pain; post-mastectomypain (see, Devers & Galer, Clin J Pain. 2000; 16(3):205-8); central pain(Cahana, A., et al., Anesth Analg. 2004; 98(6):1581-4), spinal cordinjury pain (see, Hains, B. C., et al., Exp Neurol. 2000;164(2):426-37); post-stroke pain; thalamic pain (see, LaBuda, C. J., etal., Neurosci Lett. 2000; 290(1):79-83); complex regional pain syndrome(see, Wallace, M. S., et al., Anesthesiology. 2000; 92(1):75-83; XantosD et al., J Pain. 2004; 5(3 Suppl 2):S1); phanton pain (see, Weber, W.E., Ned Tijdschr Geneeskd. 2001; 145(17):813-7; Levitt & Heyback, Pain.1981; 10(1):67-73); intractable pain (see, Yokoyama, M., et al., Can JAnaesth. 2002; 49(8):810-3); acute pain, acute post-operative pain (see,Koppert, W., et al., Anesth Analg. 2004; 98(4):1050-5; Brennan, T. J.,et al., Pain. 1996; 64(3):493-501); acute musculoskeletal pain; jointpain (see, Gotoh, S., et al., Ann Rheum Dis. 1993; 52(11):817-22);mechanical low back pain (see, Kehl, L. J., et al., Pain. 2000;85(3):333-43); neck pain; tendonitis; injury/exercise pain (see, Sesay,M., et al., Can J Anaesth. 2002; 49(2):137-43); acute visceral pain,including, abdominal pain; pyelonephritis; appendicitis; cholecystitis;intestinal obstruction; hernias; etc (see, Giambernardino, M. A., etal., Pain. 1995; 61(3):459-69); chest pain, including, cardiac Pain(see, Vergona, R. A., et al., Life Sci. 1984; 35(18):1877-84); pelvicpain, renal colic pain, acute obstetric pain, including, labor pain(see, Segal, S., et al., Anesth Analg. 1998; 87(4):864-9); cesareansection pain; acute inflammatory, burn and trauma pain; acuteintermittent pain, including, endometriosis (see, Cason, A. M., et al.,Horm Behav. 2003; 44(2):123-31); acute herpes zoster pain; sickle cellanemia; acute pancreatitis (see, Toma, H; Gastroenterology. 2000;119(5):1373-81); breakthrough pain; orofacial pain, including, sinusitispain, dental pain (see, Nusstein, J., et al., J Endod. 1998;24(7):487-91; Chidiac, J. J., et al., Eur J Pain. 2002; 6(1):55-67);multiple sclerosis (MS) pain (see, Sakurai & Kanazawa, J Neurol Sci.1999; 162(2):162-8); pain in depression (see, Greene B, Curr Med ResOpin. 2003; 19(4):272-7); leprosy pain; behcet's disease pain; adiposisdolorosa (see, Devillers & Oranje, Clin Exp Dermatol. 1999;24(3):240-1); phlebitic pain; Guillain-Barre pain; painful legs andmoving toes; Haglund syndrome; erythromelalgia pain (see,Legroux-Crespel, E., et al., Ann Dermatol Venereol. 2003;130(4):429-33); Fabry's disease pain (see, Germain, D. P., J Soc Biol.2002; 196(2):183-90); Bladder and urogenital disease, including, urinaryincontinence (see, Berggren, T., et al., J Urol. 1993; 150(5 Pt1):1540-3); hyperactivity bladder (see, Chuang, Y. C., et al., Urology.2003; 61(3):664-70); painful bladder syndrome (see, Yoshimura, N., etal., J. Neurosci. 2001; 21(21):8690-6); interstitial cyctitis (IC) (see,Giannakopoulos& Campilomatos, Arch Ital Urol Nefrol Androl. 1992;64(4):337-9; Boucher, M., et al., J Urol. 2000; 164(1):203-8); andprostatitis (see, Mayersak, J. S., Int Surg. 1998; 83(4):347-9; Keith,I. M., et al., J Urol. 2001; 166(1):323-8).

Unfortunately, as described above, the efficacy of currently used sodiumchannel blockers for the disease states described above has been to alarge extent limited by a number of side effects. These side effectsinclude various CNS disturbances such as blurred vision, dizziness,nausea, and sedation as well more potentially life threatening cardiacarrhythmias and cardiac failure. Accordingly, there remains a need todevelop additional Na channel antagonists, preferably those with higherpotency and fewer side effects.

SUMMARY OF THE INVENTION

It has now been found that compounds of this invention, andpharmaceutically acceptable compositions thereof, are useful asinhibitors of voltage-gated sodium channels. These compounds have thegeneral formula I:

or a pharmaceutically acceptable salt thereof.

These compounds and pharmaceutically acceptable compositions are usefulfor treating or lessening the severity of a variety of diseases,disorders, or conditions, including, but not limited to, acute, chronic,neuropathic, or inflammatory pain, arthritis, migraine, clusterheadaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias,epilepsy or epilepsy conditions, neurodegenerative disorders,psychiatric disorders such as anxiety and depression, myotonia,arrhythmia, movement disorders, neuroendocrine disorders, ataxia,multiple sclerosis, irritable bowel syndrome, incontinence, visceralpain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy,radicular pain, sciatica, back pain, head or neck pain, severe orintractable pain, nociceptive pain, breakthrough pain, postsurgicalpain, or cancer pain.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the present invention provides compounds of formulaI:

or a pharmaceutically acceptable salt thereof,wherein,

ring Z is a thiazole or thiadiazole optionally substituted with 0 to 2occurrences of R; and

R, R₁, R₂, R₃, and R₄ are hydrogen, C1-C6 aliphatic, aryl, C3-C8cycloaliphatic, halo, CN, NO₂, CF₃, OCF₃, OH, NH₂, NH(C1-C6 aliphatic),N(C1-C6 aliphatic)₂, COOH, COO(C1-C6 aliphatic), O(C1-C6 aliphatic),CHF₂, or CH₂F. For purposes of this invention, the chemical elements areidentified in accordance with the Periodic Table of the Elements, CASversion, Handbook of Chemistry and Physics, 75^(th) Ed. Additionally,general principles of organic chemistry are described in “OrganicChemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999,and “March's Advanced Organic Chemistry”, 5 th Ed., Ed.: Smith, M. B.and March, J., John Wiley & Sons, New York: 2001, the entire contents ofwhich are hereby incorporated by reference.

As described herein, compounds of the invention may optionally besubstituted with one or more substituents, such as are illustratedgenerally above, or as exemplified by particular classes, subclasses,and species of the invention. It will be appreciated that the phrase“optionally substituted” is used interchangeably with the phrase“substituted or unsubstituted.” In general, the term “substituted”,whether preceded by the term “optionally” or not, refers to thereplacement of hydrogen radicals in a given structure with the radicalof a specified substituent. Unless otherwise indicated, an optionallysubstituted group may have a substituent at each substitutable (i.e.,having the requisite valency available for a given substituent) positionof the group, and when more than one position in any given structure maybe substituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this invention arepreferably those that result in the formation of stable or chemicallyfeasible compounds. The term “stable”, as used herein, refers tocompounds that are not substantially altered when subjected toconditions to allow for their production, detection, and preferablytheir recovery, purification, and use for one or more of the purposesdisclosed herein. In some embodiments, a stable compound or chemicallyfeasible compound is one that is not substantially altered when kept ata temperature of 40° C. or less, in the absence of moisture or otherchemically reactive conditions, for at least a week.

The term “aliphatic” or “aliphatic group”, as used herein, means astraight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation. Unless otherwise specified,aliphatic groups contain 1-20 aliphatic carbon atoms. In someembodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. Inother embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms.In still other embodiments, aliphatic groups contain 1-6 aliphaticcarbon atoms, and in yet other embodiments aliphatic groups contain 1-4aliphatic carbon atoms. Suitable aliphatic groups include, but are notlimited to, linear or branched, substituted or unsubstituted alkyl,alkenyl, alkynyl groups. The term “cycloaliphatic” means a monocyclichydrocarbon, bicyclic, or tricyclic hydrocarbon that is completelysaturated or that contains one or more units of unsaturation, but whichis not aromatic and has a single point of attachment to the rest of themolecule. In some embodiments, “cycloaliphatic” refers to a monocyclicC₃-C₈ hydrocarbon or bicyclic C₈-C₁₂ hydrocarbon that is completelysaturated or that contains one or more units of unsaturation, but whichis not aromatic, that has a single point of attachment to the rest ofthe molecule wherein any individual ring in said bicyclic ring systemhas 3-7 members.

Unless otherwise specified, the term “heterocycle”, “heterocyclyl”,“heterocycloaliphatic”, or “heterocyclic” as used herein meansnon-aromatic, monocyclic, bicyclic, or tricyclic ring systems in whichone or more ring atoms in one or more ring members is an independentlyselected heteroatom. Heterocyclic ring can be saturated or can containone or more unsaturated bonds. In some embodiments, the “heterocycle”,“heterocyclyl”, or “heterocyclic” group has three to fourteen ringmembers in which one or more ring members is a heteroatom independentlyselected from oxygen, sulfur, nitrogen, or phosphorus, and each ring inthe ring system contains 3 to 7 ring members.

The term “heteroatom” means oxygen, sulfur, nitrogen, phosphorus, orsilicon (including, any oxidized form of nitrogen, sulfur, phosphorus,or silicon; the quaternized form of any basic nitrogen or; asubstitutable nitrogen of a heterocyclic ring, for example N (as in3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR⁺ (as inN-substituted pyrrolidinyl)).

The term “unsaturated”, as used herein, means that a moiety has one ormore units of unsaturation but is not aromatic.

The term “alkoxy”, or “thioalkyl”, as used herein, refers to an alkylgroup, as previously defined, attached to the principal carbon chainthrough an oxygen (“alkoxy”) or sulfur (“thioalkyl”) atom.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic,bicyclic, and tricyclic ring systems having a total of five to fourteenring carbon atoms, wherein at least one ring in the system is aromaticand wherein each ring in the system contains 3 to 7 ring carbon atoms.The term “aryl” may be used interchangeably with the term “aryl ring”.

The term “heteroaryl”, used alone or as part of a larger moiety as in“heteroaralkyl” or “heteroarylalkoxy”, refers to monocyclic, bicyclic,and tricyclic ring systems having a total of five to fourteen ringmembers, wherein at least one ring in the system is aromatic, at leastone ring in the system contains one or more heteroatoms, and whereineach ring in the system contains 3 to 7 ring members. The term“heteroaryl” may be used interchangeably with the term “heteroaryl ring”or the term “heteroaromatic”.

The term “alkylidene chain” refers to a straight or branched carbonchain that may be fully saturated or have one or more units ofunsaturation and has two points of attachment to the rest of themolecule.

The term “spirocycloalkylene” refers to a cycloaliphatic ring that hastwo points of attachment from the same carbon atom to the rest of themolecule.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, (Z) and (E) double bondisomers, and (Z) and (E) conformational isomers. Therefore, singlestereochemical isomers as well as enantiomeric, diastereomeric, andgeometric (or conformational) mixtures of the present compounds arewithin the scope of the invention.

Unless otherwise stated, all tautomeric forms of the compounds of theinvention are within the scope of the invention. For example, certainembodiments of compounds of formula (I), wherein hydrogen and ring Z is,e.g., thiazol-2-yl, can exist in tautomeric forms as shown below forcompounds wherein Z is thiazol-2-yl:

Thus, included within the scope of the invention are tautomers ofcompounds of formula (I), wherein ring Z is thiazole or thiadiazole,wherein the ring nitrogen atom in ring Z is amenable to a 1-3 tautomericshift (e.g., when ring Z is a thiazol-2-yl ring) or 1-5 tautomeric shift(e.g., when ring Z is a thiadiazol-2-yl ring).

Additionally, unless otherwise stated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched atoms. For example, compounds of formula(I), wherein one or more hydrogen atoms are replaced deuterium ortritium, or one or more carbon atoms are replaced by a ¹³C— or¹⁴C-enriched carbon are within the scope of this invention. Suchcompounds are useful, for example, as analytical tools, probes inbiological assays, or sodium channel blockers with improved therapeuticprofile.

In one embodiment, Z is an optionally substituted ring selected from:

In certain embodiments of the compounds of the present invention, Z isselected from:

In certain embodiments of the compounds of the present invention, Z is

In certain embodiments of the compounds of the present invention, Z is

In one embodiment, R₁, R₂, R₃, and R₄ are hydrogen, C1-C6 aliphatic,halo, CF₃, OCF₃, CHF₂, CH₂F, or —OCF₃. In another embodiment, R₁, R₂,R₃, and R₄ are hydrogen, C1-C6 aliphatic, halo, or CF₃.

In one embodiment, Z is

or

and R₁, R₂, R₃, and R₄ are hydrogen, C1-C6 aliphatic, halo, CF₃, OCF₃,CHF₂, CH₂F, or —OCF₃.

In one embodiment, Z is

and R₁, R₂, R₃, and R₄ are hydrogen, C1-C6 aliphatic, halo, or CF₃. Inanother embodiment, Z is

and R₁, R₂, R₃, and R₄ are hydrogen, C1-C6 aliphatic, halo, or CF₃.

In one embodiment, at least one of R₁, R₂, R₃, or R₄ is a halo. Inanother embodiment, at least two of R₁, R₂, R₃, or R₄ are halo. Inanother embodiment, R₁, R₂, R₃, and R₄ are hydrogen or halo. In anotherembodiment, R₁, R₂, R₃, and R₄ are H or Cl. In another embodiment, R₂and R₃ are Cl.

In one embodiment, at least one of R₁, R₂, R₃, or R₄ is CF₃. In anotherembodiment, R₁, R₂, R₃, and R₄ are hydrogen or CF₃. In anotherembodiment, R₂ is CF₃.

In one embodiment, Z is

and R₂ and R₃ are Cl. In another embodiment, Z is

and R₂ is CF₃.

In one embodiment, the present invention provides compounds of formulaIA:

wherein:

ring Z is a thiazole or thiadiazole optionally substituted with 0 to 2occurrences of R; and

R, R₁, R₂, R₃, and R₄ are hydrogen, C₁-C₆ aliphatic, aryl, C₃-C₈cycloaliphatic, halo, CN, NO₂, CF₃, OCF₃, OH, NH₂, NH(C1-C6 aliphatic),N(C1-C6 aliphatic)₂, COOH, COO(C1-C6 aliphatic), O(C1-C6 aliphatic),CHF₂, or CH₂F.

In one embodiment, Z is an optionally substituted ring selected from:

In certain embodiments of the compounds of the present invention, Z isselected from:

In certain embodiments of the compounds of the present invention, Z is

In certain embodiments of the compounds of the present invention, Z is

In one embodiment, R₁, R₂, R₃, and R₄ are hydrogen, C1-C6 aliphatic,halo, CF₃, OCF₃, CHF₂, CH₂F, or —OCF₃. In another embodiment, R₁, R₂,R₃, and R₄ are hydrogen, C1-C6 aliphatic, halo, or CF₃.

In one embodiment, Z is

or

and R₁, R₂, R₃, and R₄ are hydrogen, C1-C6 aliphatic, halo, CF₃, OCF₃,CHF₂, CH₂F, or —OCF₃.

In one embodiment, Z is

and R₁, R₂, R₃, and R₄ are hydrogen, C1-C6 aliphatic, halo, or CF₃. Inanother embodiment, Z is

and R₁, R₂, R₃, and R₄ are hydrogen, C1-C6 aliphatic, halo, or CF₃.

In one embodiment, at least one of R₁, R₂, R₃, or R₄ is a halo. Inanother embodiment, at least two of R₁, R₂, R₃, or R₄ are halo. Inanother embodiment, R₁, R₂, R₃, and R₄ are hydrogen or halo. In anotherembodiment, R₁, R₂, R₃, and R₄ are H or Cl. In another embodiment, R₂and R₃ are Cl.

In one embodiment, at least one of R₁, R₂, R₃, or R₄ is CF₃. In anotherembodiment, R₁, R₂, R₃, and R₄ are hydrogen or CF₃. In anotherembodiment, R₂ is CF₃.

Exemplary compounds of the present invention are shown below in Table 2.

TABLE 2 1

2

The compounds of the present invention may be prepared readily usingmethods known in the art. Illustrated below in Scheme 1 through Scheme 6are methods for preparing the compounds of the present invention.

Uses, Formulation and Administration

Pharmaceutically Acceptable Compositions

As discussed above, the present invention provides compounds that areinhibitors of voltage-gated sodium ion channels, and thus the presentcompounds are useful for the treatment of diseases, disorders, andconditions including, but not limited to acute, chronic, neuropathic, orinflammatory pain, arthritis, migraine, cluster headaches, trigeminalneuralgia, herpetic neuralgia, general neuralgias, epilepsy or epilepsyconditions, neurodegenerative disorders, psychiatric disorders such asanxiety and depression, myotonia, arrhythmia, movement disorders,neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowelsyndrome, and incontinence. Accordingly, in another aspect of thepresent invention, pharmaceutically acceptable compositions areprovided, wherein these compositions comprise any of the compounds asdescribed herein, and optionally comprise a pharmaceutically acceptablecarrier, adjuvant or vehicle. In certain embodiments, these compositionsoptionally further comprise one or more additional therapeutic agents.

It will also be appreciated that certain of the compounds of presentinvention can exist in free form for treatment, or where appropriate, asa pharmaceutically acceptable derivative thereof. According to thepresent invention, a pharmaceutically acceptable derivative includes,but is not limited to, pharmaceutically acceptable salts, esters, saltsof such esters, or any other adduct or derivative which uponadministration to a subject in need is capable of providing, directly orindirectly, a compound as otherwise described herein, or a metabolite orresidue thereof.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgement,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. A“pharmaceutically acceptable salt” means any non-toxic salt or salt ofan ester of a compound of this invention that, upon administration to arecipient, is capable of providing, either directly or indirectly, acompound of this invention or an inhibitorily active metabolite orresidue thereof. As used herein, the term “inhibitorily activemetabolite or residue thereof” means that a metabolite or residuethereof is also an inhibitor of a voltage-gated sodium ion channel.

Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge, et al. describe pharmaceutically acceptable saltsin detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporatedherein by reference. Pharmaceutically acceptable salts of the compoundsof this invention include those derived from suitable inorganic andorganic acids and bases. Examples of pharmaceutically acceptable,nontoxic acid addition salts are salts of an amino group formed withinorganic acids such as hydrochloric acid, hydrobromic acid, phosphoricacid, sulfuric acid and perchloric acid or with organic acids such asacetic acid, oxalic acid, maleic acid, tartaric acid, citric acid,succinic acid or malonic acid or by using other methods used in the artsuch as ion exchange. Other pharmaceutically acceptable salts includeadipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate,bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. This inventionalso envisions the quaternization of any basic nitrogen-containinggroups of the compounds disclosed herein. Water or oil-soluble ordispersable products may be obtained by such quaternization.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, loweralkyl sulfonate and aryl sulfonate.

As described above, the pharmaceutically acceptable compositions of thepresent invention additionally comprise a pharmaceutically acceptablecarrier, adjuvant, or vehicle, which, as used herein, includes any andall solvents, diluents, or other liquid vehicle, dispersion orsuspension aids, surface active agents, isotonic agents, thickening oremulsifying agents, preservatives, solid binders, lubricants and thelike, as suited to the particular dosage form desired. Remington'sPharmaceutical Sciences, Sixteenth Edition, E. W. Martin (MackPublishing Co., Easton, Pa., 1980) discloses various carriers used informulating pharmaceutically acceptable compositions and knowntechniques for the preparation thereof. Except insofar as anyconventional carrier medium is incompatible with the compounds of theinvention, such as by producing any undesirable biological effect orotherwise interacting in a deleterious manner with any othercomponent(s) of the pharmaceutically acceptable composition, its use iscontemplated to be within the scope of this invention. Some examples ofmaterials which can serve as pharmaceutically acceptable carriersinclude, but are not limited to, ion exchangers, alumina, aluminumstearate, lecithin, serum proteins, such as human serum albumin, buffersubstances such as phosphates, glycine, sorbic acid, or potassiumsorbate, partial glyceride mixtures of saturated vegetable fatty acids,water, salts or electrolytes, such as protamine sulfate, disodiumhydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zincsalts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, woolfat, sugars such as lactose, glucose and sucrose; starches such as cornstarch and potato starch; cellulose and its derivatives such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; powderedtragacanth; malt; gelatin; talc; excipients such as cocoa butter andsuppository waxes; oils such as peanut oil, cottonseed oil; saffloweroil; sesame oil; olive oil; corn oil and soybean oil; glycols; such apropylene glycol or polyethylene glycol; esters such as ethyl oleate andethyl laurate; agar; buffering agents such as magnesium hydroxide andaluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline;Ringer's solution; ethyl alcohol, and phosphate buffer solutions, aswell as other non-toxic compatible lubricants such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releasingagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator.

Uses of Compounds and Pharmaceutically Acceptable Compositions

In yet another aspect, a method for the treatment or lessening theseverity of acute, chronic, neuropathic, or inflammatory pain,arthritis, migraine, cluster headaches, trigeminal neuralgia, herpeticneuralgia, general neuralgias, epilepsy or epilepsy conditions,neurodegenerative disorders, psychiatric disorders such as anxiety anddepression, dipolar disorder, myotonia, arrhythmia, movement disorders,neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowelsyndrome, incontinence, visceral pain, osteoarthritis pain, postherpeticneuralgia, diabetic neuropathy, radicular pain, sciatica, back pain,head or neck pain, severe or intractable pain, nociceptive pain,breakthrough pain, postsurgical pain, or cancer pain is providedcomprising administering an effective amount of a compound, or apharmaceutically acceptable composition comprising a compound to asubject in need thereof.

In certain embodiments, a method of treatment or lessening the severityof stroke, cerebral ischemia, traumatic brain injury, amyotrophiclateral sclerosis, stress- or exercise induced angina, palpitations,hypertension, migraine, or abormal gastro-intestinal motility isprovided comprising administering an effective amount of a compound, ora pharmaceutically acceptable composition comprising a compound to asubject in need thereof.

In certain embodiments, a method for the treatment or lessening theseverity of acute, chronic, neuropathic, or inflammatory pain isprovided comprising administering an effective amount of a compound or apharmaceutically acceptable composition to a subject in need thereof. Incertain other embodiments, a method for the treatment or lessening theseverity of radicular pain, sciatica, back pain, head pain, or neck painis provided comprising administering an effective amount of a compoundor a pharmaceutically acceptable composition to a subject in needthereof. In still other embodiments, a method for the treatment orlessening the severity of severe or intractable pain, acute pain,postsurgical pain, back pain, tinnitis or cancer pain is providedcomprising administering an effective amount of a compound or apharmaceutically acceptable composition to a subject in need thereof.

In certain embodiments, a method for the treatment or lessening theseverity of femur cancer pain; non-malignant chronic bone pain;rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic lowback pain; neuropathic low back pain; myofascial pain syndrome;fibromyalgia; temporomandibular joint pain; chronic visceral pain,including, abdominal; pancreatic; IBS pain; chronic and acute headachepain; migraine; tension headache, including, cluster headaches; chronicand acute neuropathic pain, including, post-herpetic neuralgia; diabeticneuropathy; HIV-associated neuropathy; trigeminal neuralgia;Charcot-Marie Tooth neuropathy; hereditary sensory neuropathies;peripheral nerve injury; painful neuromas; ectopic proximal and distaldischarges; radiculopathy; chemotherapy induced neuropathic pain;radiotherapy-induced neuropathic pain; post-mastectomy pain; centralpain; spinal cord injury pain; post-stroke pain; thalamic pain; complexregional pain syndrome; phantom pain; intractable pain; acute pain,acute post-operative pain; acute musculoskeletal pain; joint pain;mechanical low back pain; neck pain; tendonitis; injury/exercise pain;acute visceral pain, including, abdominal pain; pyelonephritis;appendicitis; cholecystitis; intestinal obstruction; hernias; etc; chestpain, including, cardiac Pain; pelvic pain, renal colic pain, acuteobstetric pain, including, labor pain; cesarean section pain; acuteinflammatory, burn and trauma pain; acute intermittent pain, including,endometriosis; acute herpes zoster pain; sickle cell anemia; acutepancreatitis; breakthrough pain; orofacial pain including sinusitispain, dental pain; multiple sclerosis (MS) pain; pain in depression;leprosy pain; behcet's disease pain; adiposis dolorosa; phlebitic pain;Guillain-Barre pain; painful legs and moving toes; Haglund syndrome;erythromelalgia pain; Fabry's disease pain; bladder and urogenitaldisease, including, urinary incontinence; hyperactivity bladder; painfulbladder syndrome; interstitial cyctitis (IC); or prostatitis; complexregional pain syndrome (CRPS), type I and type II; angina-induced painis provided, comprising administering an effective amount of a compoundor a pharmaceutically acceptable composition to a subject in needthereof.

In certain embodiments of the present invention an “effective amount” ofthe compound or pharmaceutically acceptable composition is that amounteffective for treating or lessening the severity of one or more ofacute, chronic, neuropathic, or inflammatory pain, arthritis, migraine,cluster headaches, trigeminal neuralgia, herpetic neuralgia, generalneuralgias, epilepsy or epilepsy conditions, neurodegenerativedisorders, psychiatric disorders such as anxiety and depression,myotonia, arrhythmia, movement disorders, neuroendocrine disorders,ataxia, multiple sclerosis, irritable bowel syndrome, incontinence,visceral pain, osteoarthritis pain, postherpetic neuralgia, diabeticneuropathy, radicular pain, sciatica, back pain, head or neck pain,severe or intractable pain, nociceptive pain, breakthrough pain,postsurgical pain, tinnitis or cancer pain.

The compounds and compositions, according to the method of the presentinvention, may be administered using any amount and any route ofadministration effective for treating or lessening the severity of oneor more of acute, chronic, neuropathic, or inflammatory pain, arthritis,migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia,general neuralgias, epilepsy or epilepsy conditions, neurodegenerativedisorders, psychiatric disorders such as anxiety and depression,myotonia, arrhythmia, movement disorders, neuroendocrine disorders,ataxia, multiple sclerosis, irritable bowel syndrome, incontinence,visceral pain, osteoarthritis pain, postherpetic neuralgia, diabeticneuropathy, radicular pain, sciatica, back pain, head or neck pain,severe or intractable pain, nociceptive pain, breakthrough pain,postsurgical pain, tinnitis or cancer pain. The exact amount requiredwill vary from subject to subject, depending on the species, age, andgeneral condition of the subject, the severity of the infection, theparticular agent, its mode of administration, and the like. Thecompounds of the invention are preferably formulated in dosage unit formfor ease of administration and uniformity of dosage. The expression“dosage unit form” as used herein refers to a physically discrete unitof agent appropriate for the subject to be treated. It will beunderstood, however, that the total daily usage of the compounds andcompositions of the present invention will be decided by the attendingphysician within the scope of sound medical judgment. The specificeffective dose level for any particular subject or organism will dependupon a variety of factors including the disorder being treated and theseverity of the disorder; the activity of the specific compoundemployed; the specific composition employed; the age, body weight,general health, sex and diet of the subject; the time of administration,route of administration, and rate of excretion of the specific compoundemployed; the duration of the treatment; drugs used in combination orcoincidental with the specific compound employed, and like factors wellknown in the medical arts. The term “subject”, as used herein, means ananimal, preferably a mammal, and most preferably a human.

The pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, the compounds of the invention may be administeredorally or parenterally at dosage levels of about 0.01 mg/kg to about 50mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subjectbody weight per day, one or more times a day, to obtain the desiredtherapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a compound of the present invention,it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polethylene glycols and the like.

The active compounds can also be in microencapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, eardrops, and eye drops are also contemplated asbeing within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms are prepared by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

As described generally above, the compounds of the invention are usefulas inhibitors of voltage-gated sodium ion channels. In one embodiment,the compounds and compositions of the invention are inhibitors of one ormore of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8,or NaV1.9, and thus, without wishing to be bound by any particulartheory, the compounds and compositions are particularly useful fortreating or lessening the severity of a disease, condition, or disorderwhere activation or hyperactivity of one or more of NaV1.1, NaV1.2,NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, or NaV1.9 is implicatedin the disease, condition, or disorder. When activation or hyperactivityof NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, orNaV1.9 is implicated in a particular disease, condition, or disorder,the disease, condition, or disorder may also be referred to as a“NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8 orNaV1.9-mediated disease, condition or disorder”. Accordingly, in anotheraspect, the present invention provides a method for treating orlessening the severity of a disease, condition, or disorder whereactivation or hyperactivity of one or more of NaV1.1, NaV1.2, NaV1.3,NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, or NaV1.9 is implicated in thedisease state.

The activity of a compound utilized in this invention as an inhibitor ofNaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, orNaV1.9 may be assayed according to methods described generally in theExamples herein, or according to methods available to one of ordinaryskill in the art.

In certain exemplary embodiments, compounds of the invention are usefulas inhibitors of NaV1.3 and/or NaV1.1.

It will also be appreciated that the compounds and pharmaceuticallyacceptable compositions of the present invention can be employed incombination therapies, that is, the compounds and pharmaceuticallyacceptable compositions can be administered concurrently with, prior to,or subsequent to, one or more other desired therapeutics or medicalprocedures. The particular combination of therapies (therapeutics orprocedures) to employ in a combination regimen will take into accountcompatibility of the desired therapeutics and/or procedures and thedesired therapeutic effect to be achieved. It will also be appreciatedthat the therapies employed may achieve a desired effect for the samedisorder (for example, an inventive compound may be administeredconcurrently with another agent used to treat the same disorder), orthey may achieve different effects (e.g., control of any adverseeffects). As used herein, additional therapeutic agents that arenormally administered to treat or prevent a particular disease, orcondition, are known as “appropriate for the disease, or condition,being treated”. For example, exemplary additional therapeutic agentsinclude, but are not limited to: nonopioid analgesics (indoles such asEtodolac, Indomethacin, Sulindac, Tolmetin; naphthylalkanones such saNabumetone; oxicams such as Piroxicam; para-aminophenol derivatives,such as Acetaminophen; propionic acids such as Fenoprofen, Flurbiprofen,Ibuprofen, Ketoprofen, Naproxen, Naproxen sodium, Oxaprozin; salicylatessuch as Asprin, Choline magnesium trisalicylate, Diflunisal; fenamatessuch as meclofenamic acid, Mefenamic acid; and pyrazoles such asPhenylbutazone); or opioid (narcotic) agonists (such as Codeine,Fentanyl, Hydromorphone, Levorphanol, Meperidine, Methadone, Morphine,Oxycodone, Oxymorphone, Propoxyphene, Buprenorphine, Butorphanol,Dezocine, Nalbuphine, and Pentazocine). Additionally, nondrug analgesicapproaches may be utilized in conjunction with administration of one ormore compounds of the invention. For example, anesthesiologic(intraspinal infusion, neural blocade), neurosurgical (neurolysis of CNSpathways), neurostimulatory (transcutaneous electrical nervestimulation, dorsal column stimulation), physiatric (physical therapy,orthotic devices, diathermy), or psychologic (cognitivemethods-hypnosis, biofeedback, or behavioral methods) approaches mayalso be utilized. Additional appropriate therapeutic agents orapproaches are described generally in The Merck Manual, SeventeenthEdition, Ed. Mark H. Beers and Robert Berkow, Merck ResearchLaboratories, 1999, and the Food and Drug Administration website,www.fda.gov, the entire contents of which are hereby incorporated byreference.

The amount of additional therapeutic agent present in the compositionsof this invention will be no more than the amount that would normally beadministered in a composition comprising that therapeutic agent as theonly active agent. Preferably the amount of additional therapeutic agentin the presently disclosed compositions will range from about 50% to100% of the amount normally present in a composition comprising thatagent as the only therapeutically active agent.

The compounds of this invention or pharmaceutically acceptablecompositions thereof may also be incorporated into compositions forcoating an implantable medical device, such as prostheses, artificialvalves, vascular grafts, stents and catheters. Accordingly, the presentinvention, in another aspect, includes a composition for coating animplantable device comprising a compound of the present invention asdescribed generally above, and in classes and subclasses herein, and acarrier suitable for coating said implantable device. In still anotheraspect, the present invention includes an implantable device coated witha composition comprising a compound of the present invention asdescribed generally above, and in classes and subclasses herein, and acarrier suitable for coating said implantable device. Suitable coatingsand the general preparation of coated implantable devices are describedin U.S. Pat. Nos. 6,099,562; 5,886,026; and 5,304,121. The coatings aretypically biocompatible polymeric materials such as a hydrogel polymer,polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylacticacid, ethylene vinyl acetate, and mixtures thereof. The coatings mayoptionally be further covered by a suitable topcoat of fluorosilicone,polysaccarides, polyethylene glycol, phospholipids or combinationsthereof to impart controlled release characteristics in the composition.

Another aspect of the invention relates to inhibiting one or more ofNaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, orNaV1.9, activity in a biological sample or a subject, which methodcomprises administering to the subject, or contacting said biologicalsample with a compound of formula I or a composition comprising saidcompound. The term “biological sample”, as used herein, includes,without limitation, cell cultures or extracts thereof, biopsied materialobtained from a mammal or extracts thereof, and blood, saliva, urine,feces, semen, tears, or other body fluids or extracts thereof.Inhibition of one or more of NAV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5,NaV1.6, NaV1.7, NaV1.8, or NaV1.9, activity in a biological sample isuseful for a variety of purposes that are known to one of skill in theart. Examples of such purposes include, but are not limited to, thestudy of sodium ion channels in biological and pathological phenomena;and the comparative evaluation of new sodium ion channel inhibitors.

EXAMPLES

General methods. ¹H NMR (400 MHz) and ¹³C NMR (100 MHz) spectra wereobtained as solutions in deuteriochloroform (CDCl₃) or dimethylsulfoxide-D₆ (DMSO). Mass spectra (MS) were obtained using an AppliedBiosystems API EX LC/MS system equipped with a Phenomenex 50×4.60 mmluna-5μ C18 column. The LC/MS eluting system was 10-99% acetonitrile inH₂O with 0.035% v/v trifluoroacetic acid using a 4.5 minute lineargradient and a flow rate of 4.0 mL/minute. Silica gel chromatography wasperformed using silica gel-60 with a particle size of 230-400 mesh.Pyridine, dichloromethane (CH₂Cl₂), tetrahydrofuran (THF), were fromAldrich Sure-Seal bottles kept under dry nitrogen. All reactions werestirred magnetically unless otherwise noted. Unless specified otherwise,all temperatures refer to internal reaction temperatures. In the methodsbelow, Q represents

wherein R₁, R₂, R₃, and R₄ are as defined above and is generallyreferred to as “amine.”7-Trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline used in thepreparation of compound 2 was obtained commercially from either PharmLabProduct List or ASW MedChem Product List.

Synthesis of 1,2,4-Thiadiazol-5-ylamine

Method A

(E)-N′-Carbamothioyl-N,N-dimethylformimidamide

Under an N₂ atmosphere at RT, 1,1-dimethoxy-N,N-dimethylmethanamine (174mL, 150 g, 1.31 mol) was added to a mixture of thiourea (90.0 g, 1.2mol) and MeOH (950 mL), and the reaction was heated to reflux for 4 h.The mixture was allowed to cool to RT and stirred for 19 h. The reactionwas then cooled to 0° C. and stirred for 1 h. The formed precipitate wasfiltered off and washed with a 1:1 mixture of MeOH and hexanes to obtain(E)-N′-carbamothioyl-N,N-dimethylformimidamide as a white solid (133 g,85%). ¹H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.20 (s, 1H), 7.93 (s,1H), 3.13 (s, 3H), 2.99 (s, 3H). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)), m/z: M+1 obs=132.0; t_(R)=0.37 min.

1,2,4-Thiadiazol-5-ylamine

A mixture of (E)-N′-carbamothioyl-N,N-dimethylformimidamide (3.9 g, 30mmol), hydroxylamine-O-sulfonic acid (3.7 g, 33 mmol) and EtOH (100 mL)was heated at 80° C. for 8 h. After cooling to RT, triethylamine wasadded, and the mixture was stirred at RT for 19 h. The solvents wereevaporated under reduced pressure, and the residue was taken up in a 9:1mixture of CH₂Cl₂:MeOH (10 mL) and purified via silica gelchromatography using 5% MeOH in CH₂Cl₂ to obtain1,2,4-thiadiazol-5-amine as a white solid (1.4 g, 47%). ¹H NMR (400 MHz,DMSO-d₆) δ 7.95 (s, 2H), 7.85 (s, 1H). LC/MS (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=102.1; t_(R)=0.39 min.

Method B 1,2,4-Thiadiazol-5-ylamine

To a solution of formamidine (HOAc salt, 500 g, 4.8 mol) in MeOH (1500mL) was added potassium thiocyanate (465 g, 4.8 mol). After stirring atroom temperature for 10 min, a solution of sodium methoxide (520 g, 9.6mol) in MeOH (1500 mL) was added to the resulting solution at 0° C., andthen bromine (250 mL, 4.8 mol) was added dropwise to the solution at−15° C. After stirring at −10° C. for 0.5 h, 0° C. for 0.5 h, and atroom temperature for 3 h, MeOH was removed under reduced pressure. Theresidue was dissolved in EtOAc, and the insoluble material was filtered.The filtrate was poured into a saturated aqueous NaCl solution, and theaqueous layer was extracted with EtOAc. The organic layer was dried overNa₂SO₄ and evaporated under reduced pressure. The residual gum wasextracted with Et₂O to give the crude compound [1,2,4]thiadiazol-5-ylamine (221 g), which was used in the next step withoutfurther purification.

1,2,4-Thiadiazol-5-ylamine hydrochloride

To a solution of 1,2,4-thiadiazol-5-ylamine (220 g, 2.19 mol) in MeOH(1000 mL) was added solution of HCl in MeOH (4 M, 1000 mL). Afteraddition, the resulting suspension was stirred at room temperature for 1h. The solid product was collected by filtration, washed with MeOH, anddried to give 1,2,4-thiadiazol-5-amine hydrochloride (137.7 g, 21% overtwo steps). ¹H NMR (300 MHz, D₂O) δ 8.02 (s, 1H). MS (ESI) m/e (M+H⁺)101.2.

General Procedure 1

Method A

A mixture of 4-bromobenzene-1-sulfonyl chloride (1 equivalent), aminoheterocycle (1 equivalent) and pyridine (2.2-4.4 M) was stirred under anN₂ atmosphere at RT for 19 h. Purification via silica gel chromatographyusing 5% MeOH in CH₂Cl₂ gave the desired product.

Method B

A mixture of 4-bromobenzene-1-sulfonyl chloride (1 equivalent, 1 mmol),amino heterocycle (1 equivalent, 1 mmol), 1,4-diazabicyclo[2.2.2]octane(DABCO) (1 equivalent, 1 mmol) and acetonitrile (4.8 mL) was stirred atRT overnight. Purification via silica gel chromatography using MeOH inCH₂Cl₂ gave the desired products.

4-Bromo-N-(thiazol-2-yl)benzenesulfonamide

Synthesized according to General procedure 1, Method A. Yield: 99%. ¹HNMR (400 MHz, DMSO-d6) δ 7.77-7.71 (m, 4H), 7.29 (d, J=4.6 Hz, 1H), 6.87(d, J=4.6 Hz, 1H). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)),m/z: M+1 obs=319.0; t_(R)=3.22 min.

General Procedure 2

To a stirring solution of the aminoheterocycle (2.4 equivalents, 2.4mmol) and pyridine (0.35 mL) under N₂, at 0° C., was added pipsylchloride (1 equivalent, 1 mmol). The mixture was stirred at ambienttemperature for 17 hours. CH₂Cl₂/MeOH-2/1 was added. The mixture wasfiltered and the filtrate was purified via silica gel chromatographyusing MeOH in CH₂Cl₂. The solid was triturated to give the desiredproducts.

4-Iodo-N-(thiazol-2-yl)benzenesulfonamide

To a stirring solution of 2-aminothiazole (13.2 g, 132.2 mmol) andpyridine (20 mL) under N₂, at 0° C., was added pipsyl chloride (20.0 g,55.1 mmol). The mixture was stirred at ambient temperature for 17 hours.CH₂Cl₂/MeOH-2/1 (100 mL) was added. The mixture was filtered and thefiltrate was purified via silica gel chromatography using 5% MeOH inCH₂Cl₂. The solid was triturated with CH₂Cl₂ to obtain the desiredsulfonamide as a white solid (8.4 g, 20.9 mmol, 38% yield). ¹H NMR (400MHz, DMSO-d6) δ 12.83 (s, 1H), 7.94-7.90 (m, 2H), 7.57-7.54 (m, 2H),7.26 (d, J=4.6 Hz, 1H), 6.86 (d, J=4.6 Hz, 1H).

Route 1

(R)-5-(2-Hydroxyethyl)-2,2-dimethyl-1,3-dioxolan-4-one

To a stirring solution of (R)-(−)-dimethyl-5-oxo-1,2-dioxolane-4-aceticacid (15.8 g, 91 mmol), and THF (90 mL), at 0° C., under N₂, was addedborane-THF complex (1.0 M in THF, 100 mL, 100 mmol) dropwise over 60minutes. The mixture was stirred at 0° C. for 2.5 hours and then allowedto warm to 25° C. The mixture was stirred at room temperature for 19hours. The mixture was poured into MeOH (150 mL) and the solution wasevaporated to dryness under reduced pressure at 25° C. The residue waspurified via silica gel chromatography using 30% EtOAc in hexanes toobtain the desired alcohol as a clear oil (7.1 g, 44.6 mmol, 49% yield).¹H NMR (400 MHz, CDCl₃) δ 4.61-4.51 (m, 1H), 3.89-3.80 (m, 2H),2.20-2.12 (m, 2H), 2.05-1.98 (m, 1H), 1.64 (s, 3H), 1.57 (s, 3H).

(R)-3-Hydroxydihydrofuran-2(3H)-one

A solution of (R)-5-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxolan-4-one(33.0 g, 206 mmol), p-toluenesulfonic acid monohydrate (400 mg, 2.1mmol), and benzene (300 mL) was stirred at 25° C. for 3 hours. Thesolution was evaporated to dryness under reduced pressure at 25° C. Theresidue was purified via silica gel chromatography using 50% EtOAc inhexanes to give the desired lactone as a clear oil (18.0 g, 176 mmol,85% yield). ¹H NMR (400 MHz, CDCl₃) δ 4.57-4.52 (m, 1H), 4.44 (td,J=9.0, 3.6 Hz, 1H), 4.28-4.21 (m, 1H), 3.72 (s, 1H), 2.66-2.58 (m, 1H),2.35-2.24 (m, 1H).

(R)-3-(tert-butyldiphenylsilyloxy)dihydrofuran-2(3H)-one

To a stirring solution of (R)-3-hydroxydihydrofuran-2(3H)-one (41.0 g,401 mmol), imidazole (61.4 g, 920 mmol), and CH₂Cl₂ (175 mL) at 0° C.,under N₂, was added t-butyldiphenylsilyl chloride (129 mL, 138 g, 497mmol) dropwise over 30 minutes. The mixture was stirred at roomtemperature for 19 hours. The mixture was partitioned between CH₂Cl₂(700 mL) and H₂O (100 mL). The organic portion concentrated to drynessunder reduced pressure. The residue was purified via silica gelchromatography using 50% EtOAc in hexane to give the desired lactone asa white solid (127 g, 373 mmol, 93% yield). ¹H NMR (400 MHz, CDCl₃) δ7.84-7.82 (m, 2H), 7.73-7.71 (m, 2H), 7.50-7.40 (m, 6H), 4.41-4.31 (m,2H), 4.06-4.00 (m, 1H), 2.29-2.19 (m, 2H), 1.10 (s, 9H).

General Procedure 3

To a stirring suspension of the aniline (1.3 mmol) and CH₂Cl₂ (5.5 mL)under N₂, at 0° C., was added trimethylaluminum (1.3 mmol) dropwise over20 minutes. The solution was stirred at ambient temperature for 30minutes. The solution was cooled to 0° C. followed by the dropwiseaddition of (R)-3-(tert-butyldiphenylsilyloxy)dihydrofuran-2(3H)-one (1mmol) in CH₂Cl₂ (1.0 mL) over 30 minutes. The solution was stirred atambient temperature for 19 hours. The solution was cooled to 0° C. andaqueous 1.0 M HCl was added dropwise over 1.5 hours. The organic portionwas washed with 1.0 N aqueous HCl (2×1.0 mL) and evaporated to drynessunder reduced pressure. The residue was purified via silica gel usingMeOH in CH₂Cl₂ to obtain the desired amide as a white solid.

(R)-2-(tert-Butyldiphenylsilyloxy)-4-hydroxy-N-(4-(N-thiazol-2-ylsulfamoyl)phenyl)butanamide

The reaction was set up with sulfathiazole (122 g, 477 mmol), CH₂Cl₂(1.5 L), trimethylaluminum (2.0 M in hexanes, 239 mL, 477 mmol), and(R)-3-(tert-butyldiphenylsilyloxy)dihydrofuran-2(3H)-one (125 g, 367mmol) in CH₂Cl₂ (250 mL). The reaction was purified via silica gel using10% MeOH in CH₂Cl₂ to obtain the desired amide as a white solid (207 g,348 mmol, 95% yield). ¹H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 7.76(dd, J=1.8, 7.0 Hz, 1H), 7.74 (s, 1H), 7.59-7.53 (m, 4H), 7.44-7.28 (m,8H), 7.09 (d, J=4.6 Hz, 1H), 6.46 (d, J=4.6 Hz, 1H), 4.34 (dd, J=4.1,6.7 Hz, 1H), 3.64-3.59 (m, 1H), 3.54 (dd, J=6.1, 11.4 Hz, 1H), 1.99-1.91(m, 1H), 1.81-1.70 (m, 1H), 1.10 (s, 9H). LC/MS (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=596.5; t_(R)=1.93 min.

General Procedure 4

Method A

To a stirring solution of di-tert-butyl-azodicarboxylate (3.0equivalent, 3.0 mmol) and THF (2.0 mL), under N₂, at 0° C., was addedtributylphosphine (3.0 equivalent, 3.0 mmol), dropwise over 5 minutes.The colourless solution was stirred at 0° C. for 30 minutes. A solutionof amidealcohol (1.0 equivalent, 1.0 mmol) in THF (0.60 mL) was addeddropwise over 5 minutes. The solution was stirred at ambient temperaturefor 2 hours. To this solution was added H₂O (40 uL) and the solution wasevaporated to dryness. The residue was purified via silica gel usingEtOAc in hexanes to give the desired lactam.

Method B

The alcohol (1.0 equivalent, 1.0 mmol) in anhydrous DCM (4.0 mL) wasstirred and cooled down to 0° C. To this, a solution of PPh₃ (1.5equivalents, 1.5 mmol) in anhydrous DCM (0.90 mL) was slowly addedfollowed by the slow addition of CBr₄ (1.5 equivalents, 1.5 mmol) inanhydrous DCM (0.90 mL). On completion of CBr₄ addition, the reactionwas maintained at 0° C. for 5 min. The ice bath was removed and thereaction was stirred at room temperature for 4 h. The reaction wasmonitored by LCMS. The reaction was diluted with DCM and the organiclayer was washed with saturated aqueous NaHCO₃ (×2) and brine (×1). Theorganic layer was dried over Na₂SO₄ and concentrated. The crude productwas purified by column chromatography (gradient 0-100% EtOAc/Hexane) toprovide the bromide as a pale yellow solid (9.0 g). To a solution of thebromide (1.0 equivalent, 1.0 mmol) in chloroform (3.5 mL; HPLC grade),DBU (equivalents, 2.0 mmol) was added and stirred at room temperatureunder N₂ atmosphere for ˜1 h. The reaction was monitored by LCMS. Thereaction was diluted with DCM and the organic layer was washed withaqueous 1 N HCl (×3), saturated aqueous NaHCO₃ (×2) and brine (×1). Theorganic layer was dried over Na₂SO₄ and concentrated to provide thedesired lactam as a yellow solid.

(R)-4-(3-(tert-Butyldiphenylsilyloxy)-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

Synthesized according to General procedure 4, Method A. The reaction wasset up with di-tert-butyl-azodicarboxylate (1.81 g, 7.88 mmol), THF (15mL), tributylphosphine (1.59 g, 7.88 mmol), and(R)-2-(tert-butyldiphenylsilyloxy)-4-hydroxy-N-(4-(N-thiazol-2-ylsulfamoyl)phenyl)butanamide(1.56 g, 2.63 mmol). The residue was purified via silica gel using 40%EtOAc in hexanes to give the desired lactam as a white solid (1.3 g, 2.3mmol, 86% yield). ¹H NMR (400 MHz, DMSO-d6) δ 7.83-7.76 (m, 4H), 7.70(dd, J=1.9, 7.0 Hz, 2H), 7.65 (dd, J=1.5, 8.0 Hz, 2H), 7.39-7.29 (m,6H), 7.06 (d, J=4.6 Hz, 1H), 6.44 (d, J=4.6 Hz, 1H), 4.35 (dd, J=7.9,9.2 Hz, 1H), 3.67-3.62 (m, 1H), 3.48-3.42 (m, 1H), 2.18-1.98 (m, 2H)1.11 (s, 9H).

Synthesized according to General procedure 4, Method B. The reaction wasset up with(R)-2-(tert-Butyldiphenylsilyloxy)-4-hydroxy-N-(4-(N-thiazol-2-ylsulfamoyl)phenyl)butanamide(10.0 g, 16.78 mmol, 1.0 equiv.), DCM (70 mL), PPh₃ (6.6 g, 25.2 mmol,1.5 equiv.), CBr₄ (8.35 g, 25.2 mmol, 1.5 equiv.), DBU (3.53 mL, 23.58mmol, 2.0 equiv.) The organic layer was dried over Na₂SO₄ andconcentrated to provide the lactam as a yellow solid (6.25 g, 92%). ¹HNMR (400 MHz, DMSO-d6) δ 7.83-7.76 (m, 4H), 7.70 (dd, J=1.9, 7.0 Hz,2H), 7.65 (dd, J=1.5, 8.0 Hz, 2H), 7.39-7.29 (m, 6H), 7.06 (d, J=4.6 Hz,1H), 6.44 (d, J=4.6 Hz, 1H), 4.35 (dd, J=7.9, 9.2 Hz, 1H), 3.67-3.62 (m,1H), 3.48-3.42 (m, 1H), 2.18-1.98 (m, 2H) 1.11 (s, 9H).

General Procedure 5

To a stirring suspension of benzenesulfonamide (1.0 mmol) in CH₂Cl₂ (2.3mL), under N₂, at 0° C., was added N,N-diisopropylethylamine (2.0 mmol)followed by allylbromide (2.0 mmol). The mixture was stirred at ambienttemperature for 19 hours. The mixture was evaporated to dryness underreduced pressure. The residue was purified via silica gel using EtOAc inhexanes to give the desired alkylsulfonamide.

(R)—N-Allyl-4-(3-(tert-butyldiphenylsilyloxy)-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

The reaction was set up with(R)-4-(3-(tert-butyldiphenylsilyloxy)-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide(50.0 g, 86.6 mmol), CH₂Cl₂ (200 mL), N,N-diisopropylethylamine (30.2mL, 173.2 mmol), and allylbromide (15.0 mL, 173.2 mmol). The residue waspurified via silica gel using 50% EtOAc in hexanes to give the desiredsulfonamide as a white solid (45.0 g, 72.7 mmol, 84% yield). ¹H NMR (400MHz, DMSO-d6) δ. 7.85-7.79 (m, 6H), 7.70 (dd, J=1.6, 7.7 Hz, 2H),7.49-7.40 (m, 6H), 7.36 (d, J=4.7 Hz, 1H), 6.93 (d, J=4.7 Hz, 1H),5.90-5.82 (m, 1H), 5.16 (dd, J=1.3, 10.3 Hz, 1H), 4.97 (d, J=1.3 Hz,1H), 4.56-4.52 (m, 3H), 3.76-3.72 (m, 1H), 3.56-3.48 (m, 1H), 2.28-2.25(m, 1H), 2.19-1.98 (m, 1H), 1.11 (s, 9H).

(R)—N-Allyl-4-(3-hydroxy-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

To a stirring solution of(R)—N-allyl-4-(3-(tert-butyldiphenylsilyloxy)-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide(78.7 g, 127 mmol) and THF (300 mL) under N₂, at 0° C., was addedtetrabutylammonium fluoride (1.0 M in THF, 255 mL, 255 mmol) dropwiseover 20 minutes. The mixture was stirred at ambient temperature for 2hours. To this solution was added H₂O (5 mL) followed by evaporation todryness. The residue was purified via silica gel using 30% EtOAc inhexanes to obtain the desired alcohol as a white solid (39.5 g, 104mmol, 82% yield). ¹H NMR (400 MHz, DMSO-d6) δ 7.86-7.80 (m, 4H), 7.37(d, J=4.7 Hz, 1H), 6.93 (d, J=4.7 Hz, 1H), 5.92-5.83 (m, 2H), 5.17 (dd,J=1.3, 10.3 Hz, 1H), 4.98 (q, J=1.4 Hz, 1H), 4.55 (dt, J=5.3, 1.7 Hz,2H), 4.36-4.30 (m, 1H), 3.81-3.76 (m, 1H), 3.70 (td, J=9.5, 5.4 Hz, 1H),2.45-2.38 (m, 1H), 1.90-1.80 (m, 1H).

General Procedure 6

Method A

To a stirring solution of alcohol (1.0 mmol) and CH₂Cl₂ (3.0 mL) underN₂, at −40° C., was added N,N-diisopropylethylamine (2.0 mmol) followedby the dropwise addition of triflic anhydride (1.1 mmol) over 20minutes. The mixture was stirred at −40° C. for 1 hour. To this solutionwas added amine (1.5 mmol) at −40° C. The solution was held at aspecific temperature (−20° C. to 25° C.) for a specified time followedby quenching with H₂O (5.5 mmol). The reaction was evaporated to drynessunder reduced pressure. The residue was purified via silica gel usingMeOH in CH₂Cl₂ to obtain the desired lactam.

Method B

Under an N₂ atmosphere at −30° C., N,N-diisopropylethylamine (2-4equivalent) was added dropwise to a solution of alcohol (1 equivalent)in CH₃CN (0.5 M). Trifluoromethanesulfonic anhydride (1.1-2.1equivalent) was added dropwise to this solution maintaining the internaltemperature of the reaction mixture below −30° C. To 0° C. solution ofamine (1.5-3 equivalent) in CH₃CN (0.5 mL) was added dropwise, NaH (0.9equivalent to amine) in CH₃CN. Upon completion of addition, the mixturewas stirred at 0° C. for 1 h. This amine reaction mixture was added tothe above triflate mixture at −30° C. The reaction was allowed to warmup to 0° C. and was kept at this temperature for 24 h. The reactionmixture was washed with saturated aqueous sodium bicarbonate (2×),brine, dried over magnesium sulfate, and concentrated. Purification viasilica gel chromatography using 0-40% ethyl acetate in hexane gave thedesired product.

General Procedure 7

To a stirring suspension of allyl sulfonamide (1.0 mmol) and CH₃CN (3.8mL) was added Pd(PPh₃)₄ (0.2 mmol) and 1,3-dimethylbarbituric acid (10mmol). The mixture was heated at 60° C. for 4 hours. The reaction wasevaporated to dryness under reduced pressure. The residue was purifiedvia silica gel using MeOH in CH₂Cl₂ to obtain the desired sulfonamide.

Route 2

General Procedure 8

To a solution of protected TBDPS sulfonamide (1 equivalent) in THF(0.5-1 M) under N₂, was added a solution of tetrabutyl ammonium fluoridein THF (1M, 4 equivalent). Upon completion of addition, the mixture wasstirred at RT overnight. The reaction mixture was poured into water andextracted with CH₂Cl₂ (2×), dried over magnesium sulfate, andconcentrated. Purification via silica gel chromatography using 2-10%MeOH in CH₂Cl₂ gave desired product.

(R)-4-(3-Hydroxy-2-oxopyrrolidin-1-yl-N-(thiazol-2-yl)benzenesulfonamide

To a solution of(R)-4-(3-(tert-butyldiphenylsilyloxy)-2-oxopyrrolidin-1-yl-N-(thiazol-2-yl)benzenesulfonamide(5.5 g, 9.53 mmol) in THF (40 mL) under N₂, was added a solution oftetrabutyl ammonium fluoride in THF (1M, 40 mL, 38.12 mmol). Uponcompletion of addition, the mixture was stirred at RT overnight. Thereaction mixture was poured into water and extracted with CH₂Cl₂ (2×50mL), dried over magnesium sulfate, and concentrated. Purification viasilica gel chromatography using 2-10% MeOH in CH₂Cl₂ gave(R)-4-(3-hydroxy-2-oxopyrrolidin-1-yl-N-(thiazol-2-yl)benzenesulfonamide(2.6 g, 76%). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z:M+1 obs=340.0; t_(R)=0.54 min.

General Procedure 9

Method A

Under an N₂ atmosphere at −40° C., N,N-diisopropylethylamine (2-4equivalent) was added dropwise to a solution of alcohol (1 equivalent)in CH₂Cl₂ (0.5 M). Trifluoromethanesulfonic anhydride (1.1-2.1equivalent) was added dropwise to this solution maintaining the internaltemperature of the reaction mixture below −40° C. Upon completion ofaddition, the mixture was stirred at −40° C. for 1 h. A solution ofamine (1.5-3 equivalent) in CH₂Cl₂ (40 mL) was added dropwise to thissolution maintaining the internal temperature of the reaction mixturebelow −40° C. The reaction was allowed to warm up to −20° C. and waskept at this temperature for 48 h. The reaction mixture was washed withsaturated aqueous sodium bicarbonate (2×), brine, dried over magnesiumsulfate, and concentrated. Purification via silica gel chromatographyusing 0-40% ethyl acetate in hexane gave desired product.

Method B

Under an N₂ atmosphere at −30° C., N,N-diisopropylethylamine (2-4equivalent) was added dropwise to a solution of alcohol (1 equivalent)in CH₃CN (0.5 M). Trifluoromethanesulfonic anhydride (1.1-2.1equivalent) was added dropwise to this solution maintaining the internaltemperature of the reaction mixture below −30° C. To 0° C. solution ofamine (1.5-3 equivalent) in CH₃CN (0.5 mL) was added dropwise, NaH (0.9equivalent to amine) in CH₃CN. Upon completion of addition, the mixturewas stirred at 0° C. for 1 h. This amine reaction mixture was added toabove triflate mixture at −30° C. The reaction was allowed to warm up to0° C. and was kept at this temperature for 24 h. The reaction mixturewas washed with saturated aqueous sodium bicarbonate (2×), brine, driedover magnesium sulfate, and concentrated. Purification via silica gelchromatography using 0-40% ethyl acetate in hexane gave desired product.

General Procedure 10

Method A

A solution of mesylate (1 equivalent), triethylamine (3 equivalents) andamine (2-5 equivalents) in DMF (0.3-0.5 M) was stirred under an N₂atmosphere at RT for 19 h. Purification via reverse phase HPLC using10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA) gave the desired product.

Method B

A solution of mesylate (1 equivalent), potassium fluoride (1 equivalent)and amine (2-5 equivalent) in acetonitrile (0.3-0.5 M) was microwaved at150° C. for 10 min. Purification via reverse phase HPLC using 10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA) gave the desired product.

General Procedure 11

Under an N₂ atmosphere at −20° C., DMAP (1.5-3 equivalent) was added toa solution of alcohol (1 equivalent) in CH₂Cl₂ (0.5 M). To the reactionmixture then added triethylamine (3 equivalents). P-toluenesulfonicanhydride (3 equivalents) was added dropwise to this solution at −20° C.Upon completion of addition, the mixture was stirred at RT overnight.The reaction mixture was poured into water and extracted with CH₂Cl₂(2×), dried over magnesium sulfate, and concentrated. Purification viasilica gel chromatography using 2-10% MeOH in CH₂Cl₂ gave bis tosylatedalcohol.

General Procedure 12

A solution of tosylated alcohol (1 equivalent), triethylamine (4equivalents) and amine (4 equivalents) in DMF (0.3-0.5 M) was stirredunder N₂ atmosphere at 60° C. for 19 h. Purification via reverse phaseHPLC using 10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA) gave the desiredproduct.

Route 3

General Procedure 13

Under an N₂ atmosphere at −20° C., N,N-diisopropylethylamine (3 eq) wasadded dropwise to a solution of solution of(R)-(+)α-hydroxy-γ-butyrolactone (1 eq) in dichloromethane (0.5 mL).Then, trifluoromethanesulfonic anhydride (1-1.2 eq) was added dropwiseby maintaining internal temperature of the reaction mixture <−20° C.Upon completion of addition, the mixture was stirred at −20° C. for 1hour. The amine (1.5 eq) was added at −20° C. dropwise. The reaction wasallowed to warm to RT over a period of 30 minutes and continued to stirat RT for 16 hrs. The reaction mixture was diluted with 200 mL of ethylacetate and washed with saturated sodium bicarbonate (3×). The organiclayer was washed with a saturated aqueous NaCl solution (2×). Thesolution was dried over magnesium sulfate, filtered, and concentrated.Purification via silica gel chromatography using 10-30% ethyl acetate inhexane gave desired product.

General Procedure 14

To a solution of sulfathiazole (1-1.2 eq.) in CH₂Cl₂ (0.5 M) undernitrogen at RT was added a solution of trimethylaluminum in hexane(2.0M, 1-1.2 eq.) over 5 min. After stirring at RT for 20 min, asolution of the lactone (1 eq.) in CH₂Cl₂ (0.4 M) was added over 10 min.Stirring was continued for 18-36 h at RT or reflux, then the reactionmixture was cooled to 0° C. and quenched by careful addition of aqueous1M HCl. Phases were separated, and the aqueous phase was extracted withCH₂Cl₂ (2×). The combined organic extracts were dried over MgSO₄ andconcentrated. Purification via silica gel chromatography using 2-10%MeOH in CH₂Cl₂ gave the desired products.

General Procedure 15

To a yellow solution of di-tert-butyl azodicarboxylate (2-4 eq.) in THF(0.4 M) at 0° C. under N₂ was slowly added tributylphosphine (2-4 eq.),The resulting colorless solution of the Mitsunobu reagent was stirred atRT for 10 min, and then added to a solution of the amido alcohol (1 eq.)in THF (0.3 M) at 0° C. under N₂. The reaction mixture was stirred for10 min. at this temperature, and quenched by addition of a saturatedaqueous NaHCO₃ solution. EtOAc was added, the phases were separated, andthe aqueous layer was extracted with EtOAc (2×). The combined organicextracts were dried over MgSO₄ and concentrated. Purification via silicagel chromatography using EtOAc in hexane gave the desired products.

General Procedure 16

To a yellow solution of di-tert-butyl azo-dicarboxylate (2-4 eq.) in THF(0.4 M) at 0° C. under N₂ was slowly added tributylphosphine (2-4 eq.),The resulting colorless solution of the Mitsunobu reagent was stirred atRT for 10 min, and then added to a solution of the amido alcohol (1 eq.)in THF (0.3 M) at 0° C. under N₂. The reaction mixture was stirred for10 min. at this temperature, and quenched by addition of a saturatedaqueous NaHCO₃ solution. EtOAc was added, the phases were separated, andthe aqueous layer was extracted with EtOAc (2×). The combined organicextracts were dried over MgSO₄ and concentrated. Purification via silicagel chromatography using EtOAc in hexane gave the desired products.

General Procedure 17

To chlorosulfonic acid (5-30 eq.) at 0° C. under N₂ was added thephenyl-pyrrolidin-2-one (1 eq.) in portions. The reaction mixture washeated to 50-60° C. for 15-20 min. and, after cooling to RT, carefullypoured onto ice-water. EtOAc or CH₂Cl₂ were added, the phases wereseparated, and the aqueous layer was extracted with EtOAc or CH₂Cl₂(2×). The combined organic extracts were dried over MgSO₄ andconcentrated. Purification via silica gel chromatography using EtOAc inhexane gave the desired products.

General Procedure 18

Method A

A solution of the sulfonyl chloride (1 eq.),2-tert-butyl-1,1,3,3-tetramethylguanidine (5 eq.), and thiazole orthiadiazole amine (1 eq.) in acetonitrile (0.3-0.5 M) was stirred underan N₂ atmosphere at RT for 19 h. Purification via reverse phase HPLCusing 10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA) gave the desiredproduct.

Method B

A solution of the sulfonyl chloride (1 eq.), DABCO (5 eq.), and thiazoleor thiadiazole amine (1 eq.) in acetonitrile (0.3-0.5 M) was stirredunder an N₂ atmosphere at RT for 19 h. Purification via reverse phaseHPLC using 10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA) gave the desiredproduct.

Method C

A solution of the sulfonyl chloride (1 eq.), and thiazole or thiadiazoleamine (1 eq.) in pyridine (0.3-0.5 M) was stirred under an N₂ atmosphereat RT for 19 h. Purification via reverse phase HPLC using 10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA) gave the desired product.

Method D

A solution of the sulfonyl chloride (1 eq.), phosphazene baseP1-t-Bu-tris(tetramethylene) (5 eq.), and thiazole or thiadiazole amine(1 eq.) in acetonitrile (0.3-0.5 M) was stirred under an N₂ atmosphereat RT for 19 h. Purification via reverse phase HPLC using 10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA) gave the desired product.

General Procedure 19

4-Bromobenzenesulfonamide (1 eq.), pyrrolidin-2-one (1.2 eq.), copper(I) iodide (10 mol %), N,N′-dimethylethylenediamine (20 mol %), andK₂CO₃ (4 eq.) were combined in a microwave vial and set under nitrogen.NMP (0.4 M) was added, and the reaction mixture was heated to 200° C.for 30 min. using microwave irradiation. After cooling to RT, thereaction mixture was diluted with DMSO/MeOH (1:1) and purified viareverse phase HPLC using 10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA) togive the desired products.

Route 4

(R)—S-Ethyl 2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)ethanethioate

To a stirring suspension of(R)-(−)-dimethyl-5-oxo-1,2-dioxolane-4-acetic acid (3.5 g, 20 mmol), andCH₂Cl₂ (40 mL), at 0° C., under N₂, was added isovalerylchloroformate(2.9 mL, 22 mmol) dropwise over 5 minutes. The mixture was stirred at 0°C. for 10 minutes. Triethylamine (5.5 mL, 40 mmol) was added dropwise at0° C. followed by the dropwise addition of ethanethiol (3.4 mL, 44mmol). The pink mixture was stirred at 0° C. for 10 minutes. To thereaction was added Et₂O (40 mL) and the mixture was filtered. Thefiltrate was washed with 1.0 N aqueous HCl (20 mL), 0.1 N aqueous NaOH(20 mL), H₂O (20 mL) and brine (20 mL). The organic solution wasevaporated to dryness under reduced pressure to obtain the desiredthioester as a clear oil (3.4 g, 16 mmol, 82% yield). ¹H NMR (400 MHz,CDCl₃) δ 4.71-4.65 (m, 1H), 3.91-3.81 (m, 1H), 3.11-2.70 (m, 3H), 1.53(s, 3H), 1.50 (s, 3H), 0.87-0.86 (m, 3H). LC/MS (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=219.4; t_(R)=1.33 min.

General Procedure 20

To a stirring mixture of (R)—S-ethyl2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)ethanethioate (1 equivalent),10% palladium on carbon (470 mg), and CH₂Cl₂ (0.5-1 M) under N₂, at 25°C., was added triethylsilane (1.5 equivalent) dropwise over 10 minutes.The mixture was stirred at 25° C. for 1 hour. The mixture was filteredand the filtrate was evaporated to dryness under reduced pressure togive the desired aldehyde as clear oil. The aldehyde was added to astirring mixture of sulfathiazole (0.5 equivalent), MeOH (1 M), andtrifluoroacetic acid (0.1 M). To this solution was added sodiumborohydride (2.5 equivalent) portionwise over 10 minutes. The mixturewas stirred for 10 minutes and evaporated under reduced pressure. Theresidue was purified via silica gel chromatography using 5% MeOH inCH₂Cl₂ to obtain the desired amine.

(R)-4-(2-(2,2-Dimethyl-5-oxo-1,3-dioxolan-4-yl)ethylamino)-N-(thiazol-2-yl)benzenesulfonamide

To a stirring mixture of (R)—S-ethyl2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)ethanethioate (1.9 g, 8.7 mmol),10% palladium on carbon (470 mg), and CH₂Cl₂ (20 mL) under N₂, at 25°C., was added triethylsilane (2.08 mL, 13.0 mmol) dropwise over 10minutes. The mixture was stirred at 25° C. for 1 hour. The mixture wasfiltered and the filtrate was evaporated to dryness under reducedpressure to give the desired aldehyde as a clear oil (1.2 g). Thealdehyde was added to a stirring mixture of sulfathiazole (1.1 g, 4.3mmol), MeOH (25 mL), and trifluoroacetic acid (2.5 mL). To this solutionwas added sodium borohydride (813 mg, 21.4 mmol) portionwise over 10minutes. The mixture was stirred for 10 minutes and evaporated underreduced pressure. The residue was purified via silica gel chromatographyusing 5% MeOH in CH₂Cl₂ to obtain the desired amine as a white solid(1.5 g, 3.9 mmol, 45% yield). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)), m/z: M+1 obs=398.3; t_(R)=1.18 min.

General Procedure 21

A stirring solution of benzenesulfonamide (1 equivalent),p-toluenesulfonic acid monohydrate (0.1 equivalent), and THF (0.5-1 M)was stirred at 80° C. for 3 hours. The mixture was concentrated todryness under reduced pressure. The residue was purified via silica gelchromatography using 5% MeOH in CH₂Cl₂ to give the desired lactam.

(R)-4-(3-Hydroxy-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

A stirring solution of(R)-4-(2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)ethylamino)-N-(thiazol-2-yl)benzenesulfonamide(833 mg, 2.15 mmol), p-toluenesulfonic acid monohydrate (42 mg g, 0.22mmol), and THF (10 mL) was stirred at 80° C. for 3 hours. The mixturewas concentrated to dryness under reduced pressure. The residue waspurified via silica gel chromatography using 5% MeOH in CH₂Cl₂ to givethe desired lactam as a white solid (496 g, 1.4 mmol, 65% yield). ¹H NMR(400 MHz, DMSO-d6) δ 7.85 (dd, J=2.1, 6.9 Hz, 4H), 7.25 (d, J=4.6 Hz,1H), 6.82 (d, J=4.6 Hz, 1H), 5.83 (d, J=5.9 Hz, 1H), 4.32 (d, J=5.3 Hz,1H), 3.77 (dd, J=1.9, 9.0 Hz, 1H), 3.71-3.69 (m, 1H), 2.41-2.38 (m, 1H),1.84 (dd, J=9.2, 12.3 Hz, 1H).). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)), m/z: M+1 obs=340.2; t_(R)=0.50 min.

General Procedure 22

To a stirring suspension of N-benzenesulfonamide (1 equivalent) inCH₂Cl₂ (0.5-1 M), under N₂, at 0° C., was addedN,N-diisopropylethylamine (1 equivalent) followed by allylbromide (1equivalent). The mixture was stirred at ambient temperature for 19hours. The mixture was evaporated to dryness under reduced pressure. Theresidue was purified via silica gel using 50% EtOAc in hexanes to givethe desired sulfonamide.

(R)—N-Allyl-4-(3-hydroxy-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

To a stirring suspension of(R)-4-(3-hydroxy-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide(200 mg, 0.59 mmol) in CH₂Cl₂ (0.50 mL), under N₂, at 0° C., was addedN,N-diisopropylethylamine (0.10 mL, 0.59 mmol) followed by allylbromide(51 uL, 0.59 mmol). The mixture was stirred at ambient temperature for19 hours. The mixture was evaporated to dryness under reduced pressure.The residue was purified via silica gel using 50% EtOAc in hexanes togive the desired sulfonamide as a white solid (220 mg, 0.57 mmol, 96%yield). ¹H NMR (400 MHz, DMSO-d6) δ 7.86-7.80 (m, 4H), 7.37 (d, J=4.7Hz, 1H), 6.93 (d, J=4.7 Hz, 1H), 5.92-5.83 (m, 2H), 5.17 (dd, J=1.3,10.3 Hz, 1H), 4.98 (q, J=1.4 Hz, 1H), 4.55 (dt, J=5.3, 1.7 Hz, 2H),4.36-4.30 (m, 1H), 3.81-3.76 (m, 1H), 3.70 (td, J=9.5, 5.4 Hz, 1H),2.45-2.38 (m, 1H), 1.90-1.80 (m, 1H).

General Procedure 23

Under an N₂ atmosphere at −78° C., 2,2,2-trifluoroacetic anhydride (1equivalent) was added dropwise to a solution of the aniline (1equivalent), triethylamine (1 equivalent), and CH₂Cl₂ (0.6 M). Thereaction was allowed to warm to RT over a period of 30 minutes. Afterevaporating the solvents under reduced pressure, purification via silicagel chromatography using 7/3 hexanes/EtOAc gave desired product.

General Procedure 24

A mixture of acetamide (1 equivalent) and chlorosulfonic acid (5equivalent) was heated at 155° C. for 15 min. After cooling to RT, themixture was poured into ice water and extracted with EtOAc. The organiclayer was concentrated and purified via silica gel chromatography using7/3 hexanes/EtOAc to give the desired product.

General Procedure 25

Under an N₂ atmosphere, a mixture of the sulfonyl chloride (1 mmol),amine (1 mmol), and pyridine (1.0 mL) was stirred at RT for 19 h. Thecrude product was purified via silica gel chromatography using MeOH inCH₂Cl₂.

General Procedure 26

A solution of sulfonamide (1 equivalent), NaOH (10 equivalents), and H₂O(0.25 M) was stirred at RT for 1 h, then cooled to 0° C. Acetic acid (10equivalents) was added, and the reaction was stirred at 0° C. for 20min. The formed precipitate was filtered off and dried under vacuum togive the desired product.

General Procedure 27

To a solution of sulfathiazole (1-1.2 eq.) in CH₂Cl₂ (0.5 M) undernitrogen at RT was added a solution of trimethylaluminum in hexane(2.0M, 1-1.2 eq.) over 5 min. After stirring at RT for 20 min, asolution of the lactone (1 eq.) in CH₂Cl₂ (0.4 M) was added over 10 min.Stirring was continued for 18-36 h at RT or reflux, then the reactionmixture was cooled to 0° C. and quenched by careful addition of aqueous1M HCl. Phases were separated, and the aqueous phase was extracted withCH₂Cl₂ (2). The combined organic extracts were dried over MgSO₄ andconcentrated. Purification via HPLC gave the desired product.

General Procedure 28

To a yellow solution of di-tert-butyl azodicarboxylate (2-4 eq.) in THF(0.4 M) at 0° C. under N₂ was slowly added tributylphosphine (2-4 eq.),The resulting colorless solution of the Mitsunobu reagent was stirred atRT for 10 min, and then added to a solution of the amido alcohol (1 eq.)in THF (0.3 M) at 0° C. under N₂. The reaction mixture was stirred for10 min. at this temperature, and quenched by addition of a saturatedaqueous NaHCO₃ solution. EtOAc was added, the phases were separated, andthe aqueous layer was extracted with EtOAc (2×). The combined organicextracts were dried over MgSO₄ and concentrated. Purification via HPLCgave the desired product.

Route 5

General Procedure 29

To a stirring solution of sulfonamide (1 eq.) and DMF (0.6 M), under N₂,at 5° C. (ice bath) was added N,N-diisopropylethylamine (1 eq.). To thissolution was added 4-fluorobenzenesulfonyl chloride (1 eq.) portionwiseover 10 minutes. The solution was stirred at ambient temperature for 20minutes. To this solution was added MeOH. The mixture was cooled to 5°C. via an ice bath and stirred for 30 minutes. The resulting precipitatewas filtered, washed with MeOH, and vacuum dried to afford the desiredbissulfonamide.

((R)-4-fluoro-N-(4-(3-hydroxy-2-oxopyrrolidin-1-yl)phenylsulfonyl)-N-(thiazol-2-yl)benzenesulfonamide

To a stirring solution of(R)-4-(3-hydroxy-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide(5.0 g, 14.8 mmol) and DMF (25 mL), under N₂, at 5° C. (ice bath) wasadded diisopropylethyamine (2.5 mL, 14.8 mmol). To this solution wasadded 4-fluorobenzenesulfonyl chloride (2.9 g, 14.8 mmol) portionwiseover 10 minutes. The solution was stirred at ambient temperature for 20minutes. To this solution was added MeOH (75 mL). The mixture was cooledto 5° C. via an ice bath and stirred for 30 minutes. The precipitate wasfiltered, washed with MeOH (20 mL), and vacuum dried to give the desiredsulfonamide as a white solid (6.5 g, 13.1 mmol, 89% yield). ¹H-NMR (400MHz, DMSO) δ 8.03-7.96 (m, 2H), 7.83-7.80 (m, 2H), 7.72 (d, J=5.1 Hz,1H), 7.61 (dd, J=1.8, 7.1 Hz, 1H), 7.59 (s, 1H), 7.37 (s, 1H), 7.37 (dd,J=2.0, 15.6 Hz, 1H), 7.02 (d, J=5.1 Hz, 1H), 5.88 (d, J=5.9 Hz, 1H),4.38-4.32 (m, 1H), 3.83-3.78 (m, 1H), 3.71 (td, J=9.5, 5.4 Hz, 1H),2.52-2.42 (m, 1H), 1.87 (td, J=9.4, 4.1 Hz, 1H). LC/MS (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=498.3; t_(R)=1.32 min.

General Procedure 30

Method A. A stirring suspension of the alcohol (1.0 mmol, 1.0 eq.),N,N-diisopropylethylamine (3.0 mmol, 3.0 eq.), and CH₂Cl 2 (5.0 mL),under N₂, was cooled to −20° C. Triflic anhydride (1.5 mmol, 1.5 eq.)was added dropwise over 10 minutes. The suspension was stirred at −20°C. for 1 hour. A solution of amine (1.0 mmol, 1.0 eq.) and CH₂Cl₂ (2.0mL) was added dropwise over 5 minutes. The mixture was stirred at −20°C. for 1.5 hours. Morpholine (2.0 mmol, 2.0 equivalents) was addeddropwise over 5 minutes. The mixture was stirred at −20° C. for 2 hours.The solution was allowed to warm to room temperature and concentrated todryness under reduced pressure. The residue was purified via silica gelchromatography to obtain the desired product.

Method B. A stirring suspension of the alcohol (1.0 mmol, 1 eq.),N,N-diisopropylethylamine (2.0 mmol, 2 eq.), and CH₂Cl 2 (7.5 mL), underN₂, was cooled to −40° C. Triflic anhydride (1.1 mmol, 1.1 eq.) wasadded dropwise over 10 minutes. The suspension was stirred at −40° C.for 1 hour. A solution of the amine (1.5 mmol, 1.5 eq.) and CH₂Cl₂ (0.5mL) was added dropwise over 10 minutes. The mixture was allowed toslowly warm to room temperature over 6 hours. Water (20 μL) was addedand the mixture was filtered through a bed of silica gel (5 g) followedby CH₂Cl₂ (20 mL). The filtrate was evaporated to dryness under reducedpressure. The residue was dissolved in anhydrous THF (5 mL). To thisstirring solution, under N₂, at 25° C., was added tetrabutylammoniumfluoride (1.0 M in THF, 1.0 mmol, 1 eq.) in a single portion. Thesolution was stirred at 25° C. for 30 minutes and then concentrated todryness under reduced pressure. The residue was purified via silica gelchromatography to afford the product.

Method C. A solution of the alcohol (1.0 mmol, 1 eq.) in DCM (5 mL) wasstirred under nitrogen at −20° C. To the reaction mixture was addedN,N-diisopropylethyl amine (2.0 mmol, 2 eq.) followed by dropwiseaddition of triflic anhydride (1.2 mmol, 1.2 eq.). The reaction wasstirred at −20° C. for 1 hour. A solution of the amine (1.5 mmol, 1.5eq.) and sodium hydride (60% dispersion in mineral oil, 0.9 mmol, 0.9eq.) in DCM (1.25 mL) was added to the reaction mixture and stirring wascontinued at −20° C. The reaction was allowed to warm to roomtemperature and stirred overnight. The reaction mixture was cooled to−20° C. Morpholine (2.0 mmol, 2 eq.) was added to the reaction mixtureand stirring was continued under nitrogen at −20° C. for 1 hour. Thereaction was purified by silica gel column chromatography to afford thedesired product.

General Procedure 31

To a solution of the alcohol (1.0 mmol, 1 eq.) in dichloromethane (3 mL)at −40° C. under nitrogen was added N,N-diisopropylethylamine (3.0 mmol,3 eq.), followed by trifluoromethanesulfonic anhydride (2.0 mmol, 2eq.). The reaction was stirred for 1 h, keeping the temperature between−40° C. and −50° C. A solution of the amine (1.5 mmol, 1.5 eq.) indichloromethane (1.5 mL) was added. The reaction was allowed to slowlywarm to room temperature and was stirred overnight. Purification of thecrude material was carried out using silica gel chromatography to affordthe desired product.

General Procedure 32

To a solution of the bissulfonamide (1.0 mmol, 1 eq.) in anhydrousacetonitrile (10 mL) was added morpholine (2.0 mmol, 2 eq.) dropwise atroom temperature. The reaction mixture was stirred for 15 min, then thesolvent was removed and the residue obtained was purified by silica gelcolumn chromatography to afford the product.

2-(3,4-dichlorophenyl)-ethylamine

Method A. A solution of 3,4-dichlorophenylacetonitrile (3.001 g, 16.13mmol) in ethanol (33 mL) and 29% NH₄OH (6.7 ml, 611.2 mg, 17.44 mmol) inthe presence of Raney Ni (333 mg, 3.887 mmol) was stirred vigorouslyunder H₂ (1 atm) for 6 h. The reaction mixture was filtered throughCelite then the filtrate was concentrated under reduced pressure to give2-(3,4-dichlorophenyl)ethylamine (2.82 g, 92%) as a pale yellow oil.LC/MS ((10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=190.3;t_(r)=0.80 min.

Method B. To a stirred suspension of sodium borohydride (10.17 g, 0.2688mol) in anhydrous tetrahydrofuran (160 ml) under N₂ at 0° C. was added asolution of trifluoroacetic acid (30.65 g, 20.71 ml, 0.2688 mol) inanhydrous tetrahydrofuran (25 ml) dropwise over 30 minutes. The mixturewas stirred at 10° C. for 10 minutes. A solution of2-(3,4-dichlorophenyl)acetonitrile (50 g, 0.268 mol) in anhydroustetrahydrofuran (50 ml) was added dropwise over 30 minutes. The mixturewas stirred at room temperature for 1 hour and then poured slowly onto500 g of crushed ice. The mixture was extracted three times withdichloromethane (300 ml). The organic phases were combined, washed threetimes with aqueous saturated NaHCO₃ (250 ml) and once with water (250ml), dried over sodium sulfate and concentrated under reduced pressureto provide a yellow oil as the crude product (56 g). This crude productwas dissolved in dichloromethane (560 ml, 10 ml/g) and extracted threetimes with 2 M HCl solution (300 ml). The combined aqueous layers werewashed with dichloromethane (300 ml), basified to pH 10 by addition of 1M NaOH at 0° C. then extracted three times with dichloromethane (500ml). The combined organic phases containing the product were dried oversodium sulfate, filtered, and concentrated under reduced pressure toprovide the desired 2-(3,4-dichlorophenyl)ethylamine free base as alight yellow oil (32.07 g, 62% yield).

N-(3,4-dichlorophenethyl)-2,2,2-trifluoroacetamide

2-(3,4-dichlorophenyl)ethylamine (2.82 g, 14.84 mmol) in THF (3 mL) wasadded to a neat solution of trifluoroacetic anhydride (8.5 mL, 61.15mmol) dropwise at 0° C. The reaction mixture was stirred for 3 h at roomtemperature, then quenched by addition of water (10 ml) at 0° C. Thesolvent was removed under reduced pressure and the crude product waspurified by silica gel chromatography (120 g, gradient 5-60% AcOEt inhexanes) to give N-(3,4-dichlorophenethyl)-2,2,2-trifluoroacetamide(2.86 g, 67%) as a white solid. LC/MS ((10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)), m/z: M+1 obs=286.1; t_(R)=1.74 min. ¹H NMR (400 MHz,CDCl₃) δ ppm: 7.40 (d, J=8.2 Hz, 1H), 7.31 (d, J=2.1 Hz, 1H), 7.03 (dd,J=2.1, 8.2 Hz, 1H), 6.37 (s, 1H), 3.60 (dd, J=6.8, 13.6 Hz, 2H) and 2.86(dd, J=7.1, 7.1 Hz, 2H).

6,7-dichloro-3,4-dihydroisoquinoline-N-trifluoroacetamide

N-(3,4-dichlorophenethyl)-2,2,2-trifluoroacetamide (2.860 g, 10.0 mmol)and paraformaldehyde (453 mg, 15.1 mmol) were placed in a round-bottomflask. A mixture composed of H₂SO₄ (20 mL) and AcOH (13 mL) was added atroom temperature in one portion. The reaction mixture was stirred for 8h at room temperature. The mixture was poured into ice-water (230 mL)and extracted with EtOAc (3×40 mL). The organic phases were combined,washed with water (25 mL), aqueous saturated NaHCO₃ (25 mL), brine (25mL), and then dried over sodium sulfate, filtered, and concentrated. Theresidue obtained was purified by silica gel column chromatography(gradient 1-45% EtOAc in hexanes, 120 g) providing6,7-dichloro-3,4-dihydroisoquinoline-N-trifluoroacetamide (1.3 g, 44%)and 7,8-dichloro-3,4-dihydroisoquinoline-N-trifluoroacetamide (652 mg,22%) as mixture of products (ratio was determined by NMR). LC/MS((10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=298.3;t_(R)=1.95 min.

6,7-dichloro-3,4-dihydroisoquinoline

6,7-dichloro-3,4-dihydroisoquinoline-N-trifluoroacetamide (1.95 g, 6.5mmol) was partially dissolved in methanol (45 mL) and water (12 mL).K₂CO₃ (4.77 g, 34.5 mmol) was added in one portion and the reactionmixture was stirred at 90° C. for 1 h. The solvent was removed underreduced pressure, and the residue obtained was partitioned between DCM(23 mL) and water (34 mL). The organic phase was separated and theaqueous phase was further extracted twice with DCM (23 mL). The organicphases were combined, washed with brine (23 mL), dried (Na₂SO₄),filtered and concentrated under reduced pressure.

Purification Method A The crude residue obtained was redissolved inmethanol (100 mL) and 1 M HCl (100 mL). The solvent was removed underreduced pressure providing the hydrochloride salt (2.80 g).

550 mg of 6,7-dichloro-1,2,3,4-tetrahydroisoquinoline HCl salt wereobtained by selective precipitation from methanol using AcOEt asfollows: 2.8 g of the HCl salt mixture previously obtained weredissolved in the minimum of methanol (35 mL). AcOEt (50 mL) was addeduntil a white precipitate started to form. The precipitation was allowedto occur for 10 min after which the precipitate was collected byfiltration (ratio of 6,7-dichloro analog over 7,8-dichloro analog: 95/5by NMR). The precipitate was redissolved in methanol and theprecipitation was repeated once (ratio of 6,7-dichloro analog over7,8-dichloro analog: 98.5/1.5). The mother liquor was concentrated underreduced pressure and the sequence of precipitations was repeated.

6,7-dichloro-1,2,3,4-tetrahydroisoquinoline HCl salt (550 mg, 2.31 mmol)was dissolved in water (5 mL) and DCM (20 mL). Aqueous saturated NaHCO₃(10 mL) was added and the organic phase was separated. The aqueous phasewas extracted twice with DCM (20 mL), the organic phases were combined,dried (Na₂SO₄), and filtered to give6,7-dichloro-1,2,3,4-tetrahydro-isoquinoline (470 mg, quant.).

Purification Method B The crude free base residue obtained was purifiedby silica-gel column chromatography (120 g, 4% MeOH in DCM) providing6,7-dichloro-1,2,3,4-tetrahydroisoquinoline (3.0 g, 47%).

hu 1H NMR (400 MHz, CDCl₃) δ ppm: 7.20 (s, 1H), 7.12 (s, 1H), 3.96 (s,2H), 3.12 (dd, J=6.0, 6.0 Hz, 2H) and 2.75 (dd, J=5.9, 5.9 Hz, 2H).LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=202.3;t_(R)=0.82 min.

(S)-4-(3-(6,7-dichloro-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

To a suspension of hydroxy gamma lactam (613 mg, 1.23 mmol) in anhydrousDCM (4 mL) was added DIEA (477 mg, 0.64 mL, 3.70 mmol). The mixture wascooled to −25° C. and triflic anhydride (694 mg, 0.41 mL, 2.46 mmol) wasadded dropwise. The reaction mixture was stirred at this temperature for1 h, then 6,7-dichloro-1,2,3,4-tetrahydroisoquinoline (373 mg, 1.85mmol) was added dropwise in DCM (2 mL). After 3 h at −25° C., a solutionof morpholine (0.21 ml, 2.46 mmol) was added dropwise and the coolingbath was removed. The reaction mixture was stirred for another 1 h atroom temperature then concentrated in the presence of Celite. The Celiteobtained was washed with 0.5% MeOH in DCM until all dark coloration waseluted, then purified by silica-gel column chromatography (40 g,gradient 0.5-10% MeOH in DCM) providing the final product (68 mg, 61%).¹H NMR (400 MHz, DMSO-d6) δ: 12.73 (s, 1H), 7.83 (dd, J=9.1, 20.5 Hz,4H), 7.39 (d, J=8.0 Hz, 2H), 7.25 (d, J=4.6 Hz, 1H), 6.82 (d, J=4.6 Hz,1H), 4.03 (d, J=15.4 Hz, 1H), 3.90-3.70 (m, 4H), 3.08-3.05 (m, 1H),2.82-2.76 (m, 3H), 2.32-2.24 (m, 1H), 2.16-2.08 (m, 1H). LC/MS (10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA)), m/z: M+1 obs=523.1; t_(R)=1.17 min.

(S)-4-(2-oxo-3-(7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)pyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide

A solution of(R)-4-fluoro-N-(4-(3-hydroxy-2-oxopyrrolidin-1-yl)phenylsulfonyl)-N-(thiazol-2-yl)benzenesulfonamide(12.4 g, 24.9 mmol) in DCM (80 mL) was stirred under nitrogen at −25° C.To the reaction mixture was added DIEA (9.6 g, 13 mL, 74.6 mmol)followed by dropwise addition of triflic anhydride (10.5 g, 6.30 mL,37.3 mmol). The reaction mixture was stirred at −25° C. for 90 minutes.A solution of 7-trifluoromethyl-tetrahydroisoquinoline (5.0 g, 24.9mmol) in DCM (10 mL) was added to the reaction mixture and stirring wascontinued under nitrogen at −25° C. for 1 h. Morpholine (4.33 g, 4.3 mL,49.7 mmol) was added and the cooling bath was removed. The reactionmixture was stirred at room temperature for 30 minutes, concentratedunder reduced pressure and purified by silica gel column chromatography(0.5-10% MeOH in DCM). The product obtained was taken up in DCM andprecipitated by addition of Et₂O providing a white solid (5.25 g, 40%),which was collected by filtration. ¹H NMR (400 MHz, DMSO-d6) δ: 12.0 (s,1H), 7.84 (dd, J=9.0, 22.8 Hz, 4H), 7.46 (bs, 2H), 7.32-7.30 (m, 1H),7.26 (d, J=4.6 Hz, 1H), 6.83 (d, J=4.6 Hz, 1H), 4.12 (d, J=15.3 Hz, 1H),3.92-3.78 (m, 4H), 3.15-3.10 (m, 1H), 2.90-2.83 (m, 3H), 2.34-2.27 (m,1H) and 2.19-2.10 (m, 1H). LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05%TFA)), m/z: M+1 obs=523.3; t_(R)=1.18 minMS (ESI) m/e (M+H⁺) 523.3,retention time: 1.18 min (10-99% CH₃CN in H₂O).

Table 3 below recites the analytical data for the compounds of Table 2above.

TABLE 3 Cmpd LC/MS LC/RT No. M + 1 min HNMR 1 523 1.18 δ ppm: 12.73 (s,1H), 7.83 (dd, J = 9.1, 20.5 Hz, 4H), 7.39 (d, J = 8.0 Hz, 2H), 7.25 (d,J = 4.6 Hz, 1H), 6.82 (d, J = 4.6 Hz, 1H), 4.03 (d, J = 15.4 Hz, 1H),3.90-3.70 (m, 4H), 3.08-3.05 (m, 1H), 2.82-2.76 (m, 3H), 2.32-2.24 (m,1H), 2.16-2.08 (m, 1H) 2 523 1.16 δ ppm: 12.70 (s, 1H), 7.84 (dd, J =9.0, 22.8 Hz, 4H), 7.46 (bs, 2H), 7.32-7.30 (m, 1H), 7.26 (d, J = 4.6Hz, 1H), 6.83 (d, J = 4.6 Hz, 1H), 4.12 (d, J = 15.3 Hz, 1H), 3.92-3.78(m, 4H), 3.15-3.10 (m, 1H), 2.90-2.83 (m, 3H), 2.34-2.27 (m, 1H) and2.19-2.10 (m, 1H)

Assays for Detecting and Measuring NaV Inhibition Properties of CompoundOptical Methods for Assaying NaV Inhibition Properties of Compounds:

Compounds of the invention are useful as antagonists of voltage-gatedsodium ion channels. Antagonist properties of test compounds wereassessed as follows. Cells expressing the NaV of interest were placedinto microtiter plates. After an incubation period, the cells werestained with fluorescent dyes sensitive to the transmembrane potential.The test compounds were added to the microtiter plate. The cells werestimulated with either a chemical or electrical means to evoke a NaVdependent membrane potential change from unblocked channels, which wasdetected and measured with trans-membrane potential-sensitive dyes.Antagonists were detected as a decreased membrane potential response tothe stimulus. The optical membrane potential assay utilizedvoltage-sensitive FRET sensors described by Gonzalez and Tsien (See,Gonzalez, J. E. and R. Y. Tsien (1995) “Voltage sensing by fluorescenceresonance energy transfer in single cells” Biophys J 69(4): 1272-80, andGonzalez, J. E. and R. Y. Tsien (1997) “Improved indicators of cellmembrane potential that use fluorescence resonance energy transfer” ChemBiol 4(4): 269-77) in combination with instrumentation for measuringfluorescence changes such as the Voltage/Ion Probe Reader (VIPR®) (SeeGonzalez, J. E., K. Oades, et al. (1999) “Cell-based assays andinstrumentation for screening ion-channel targets” Drug Discov Today4(9): 431-439).

VIPR® Optical Membrane Potential Assay Method with Chemical Stimulation

Cell Handling and Dye Loading

24 hours before the assay on VIPR, CHO cells endogenously expressing aNaV1.2 type voltage-gated NaV are seeded in 96-well poly-lysine coatedplates at 60,000 cells per well. Other subtypes are performed in ananalogous mode in a cell line expressing the NaV of interest.

-   -   1) On the day of the assay, medium is aspirated and cells are        washed twice with 225 μL of Bath Solution #2 (BS#2).    -   2) A 15 uM CC2-DMPE solution is prepared by mixing 5 mM coumarin        stock solution with 10% Pluronic 127 1:1 and then dissolving the        mix in the appropriate volume of BS#2.    -   3) After bath solution is removed from the 96-well plates, the        cells are loaded with 80 μL of the CC2-DMPE solution. Plates are        incubated in the dark for 30 minutes at room temperature.    -   4) While the cells are being stained with coumarin, a 15 μL        oxonol solution in BS#2 is prepared. In addition to DiSBAC₂(3),        this solution should contain 0.75 mM ABSC1 and 30 μL veratridine        (prepared from 10 mM EtOH stock, Sigma #V-5754).    -   5) After 30 minutes, CC2-DMPE is removed and the cells are        washed twice with 225 μL of BS#2. As before, the residual volume        should be 40 μL.    -   6) Upon removing the bath, the cells are loaded with 80 μL of        the DiSBAC₂(3) solution, after which test compound, dissolved in        DMSO, is added to achieve the desired test concentration to each        well from the drug addition plate and mixed thoroughly. The        volume in the well should be roughly 121 μL. The cells are then        incubated for 20-30 minutes.    -   7) Once the incubation is complete, the cells are ready to be        assayed on VIPR® with a sodium add back protocol. 120 μL of Bath        solution #1 is added to stimulate the NaV dependent        depolarization. 200 μL tetracaine was used as an antagonist        positive control for block of the NaV channel.

Analysis of VIPR® Data:

Data are analyzed and reported as normalized ratios ofbackground-subtracted emission intensities measured in the 460 nm and580 nm channels. Background intensities are then subtracted from eachassay channel. Background intensities are obtained by measuring theemission intensities during the same time periods from identicallytreated assay wells in which there are no cells. The response as afunction of time is then reported as the ratios obtained using thefollowing formula:

${R(t)} = \frac{\left( {{intensity}_{460\mspace{11mu} {nm}} - {background}_{460\mspace{11mu} {nm}}} \right)}{\left( {{intensity}_{580\mspace{11mu} {nm}} - {background}_{580\mspace{11mu} {nm}}} \right)}$

The data is further reduced by calculating the initial (R_(i)) and final(R_(f)) ratios. These are the average ratio values during part or all ofthe pre-stimulation period, and during sample points during thestimulation period. The response to the stimulus

=R_(f)/R_(i) is then calculated. For the Na⁺ addback analysis timewindows, baseline is 2-7 sec and final response is sampled at 15-24 sec.

Control responses are obtained by performing assays in the presence of acompound with the desired properties (positive control), such astetracaine, and in the absence of pharmacological agents (negativecontrol). Responses to the negative (N) and positive (P) controls arecalculated as above. The compound antagonist activity A is defined as:

$A = {\frac{R - P}{N - P}*100.}$

where R is the ratio response of the test compoundSolutions [mM]

Bath Solution #1: NaCl 160, KCl 4.5, CaCl₂ 2, MgCl₂ 1, HEPES 10, pH 7.4with NaOH

Bath Solution #2 TMA-Cl 160, CaCl₂ 0.1, MgCl₂ 1, HEPES 10, pH 7.4 withKOH (final K concentration ˜5 mM)

CC2-DMPE: prepared as a 5 mM stock solution in DMSO and stored at −20°C.

DiSBAC₂(3): prepared as a 12 mM stock in DMSO and stored at −20° C.

ABSC1: prepared as a 200 mM stock in distilled H₂O and stored at roomtemperature

Cell Culture

CHO cells are grown in DMEM (Dulbecco's Modified Eagle Medium; GibcoBRL#10569-010) supplemented with 10% FBS (Fetal Bovine Serum, qualified;GibcoBRL #16140-071) and 1% Pen-Strep (Penicillin-Streptomycin; GibcoBRL#15140-122). Cells are grown in vented cap flasks, in 90% humidity and10% CO₂, to 100% confluence. They are usually split by trypsinization1:10 or 1:20, depending on scheduling needs, and grown for 2-3 daysbefore the next split.

VIPR® Optical Membrane Potential Assay Method with ElectricalStimulation

The following is an example of how NaV1.3 inhibition activity ismeasured using the optical membrane potential method#2. Other subtypesare performed in an analogous mode in a cell line expressing the NaV ofinterest.

HEK293 cells stably expressing NaV1.3 are plated into 96-well microtiterplates. After an appropriate incubation period, the cells are stainedwith the voltage sensitive dyes CC2-DMPE/DiSBAC2(3) as follows.

Reagents

100 mg/mL Pluronic F-127 (Sigma #P2443), in dry DMSO

10 mM DiSBAC₂(3) (Aurora #00-100-010) in dry DMSO

10 mM CC2-DMPE (Aurora #00-100-008) in dry DMSO

200 mM ABSC1 in H₂O

Hank's Balanced Salt Solution (Hyclone #SH30268.02) supplemented with 10mM HEPES (Gibco #15630-080)

Loading Protocol

2×CC2-DMPE=20 μM CC2-DMPE: 10 mM CC2-DMPE is vortexed with an equivalentvolume of 10% pluronic, followed by vortexing in required amount of HBSScontaining 10 mM HEPES. Each cell plate will require 5 mL of 2×CC2-DMPE.50 μL of 2×CC2-DMPE is to wells containing washed cells, resulting in a10 μM final staining concentration. The cells are stained for 30 minutesin the dark at RT.

2× DISBAC₂(3) with ABSC1=6 μM DISBAC₂(3) and 1 mM ABSC1: The requiredamount of 10 mM DISBAC₂(3) is added to a 50 ml conical tube and mixedwith 1 μL 10% pluronic for each mL of solution to be made and vortexedtogether. Then HBSS/HEPES is added to make up 2× solution. Finally, theABSC1 is added.

The 2× DiSBAC₂(3) solution can be used to solvate compound plates. Notethat compound plates are made at 2× drug concentration. Wash stainedplate again, leaving residual volume of 50 μL. Add 50 uL/well of the 2×DiSBAC₂(3) w/ABSC1. Stain for 30 minutes in the dark at RT.

The electrical stimulation instrument and methods of use are describedin ION Channel Assay Methods PCT/US01/21652, herein incorporated byreference. The instrument comprises a microtiter plate handler, anoptical system for exciting the coumarin dye while simultaneouslyrecording the coumarin and oxonol emissions, a waveform generator, acurrent- or voltage-controlled amplifier, and a device for insertingelectrodes in well. Under integrated computer control, this instrumentpasses user-programmed electrical stimulus protocols to cells within thewells of the microtiter plate.

Reagents

Assay buffer #1

140 mM NaCl, 4.5 mM KCl, 2 mM CaCl₂, 1 mM MgCl₂, 10 mM HEPES, 10 mMglucose, pH 7.40, 330 mOsm

Pluronic stock (1000×): 100 mg/mL pluronic 127 in dry DMSO

Oxonol stock (3333×): 10 mM DiSBAC₂(3) in dry DMSO

Coumarin stock (1000×): 10 mM CC2-DMPE in dry DMSO

ABSC1 stock (400×): 200 mM ABSC1 in water

Assay Protocol

Insert or use electrodes into each well to be assayed.

Use the current-controlled amplifier to deliver stimulation wave pulsesfor 3 s. Two seconds of pre-stimulus recording are performed to obtainthe un-stimulated intensities. Five seconds of post-stimulationrecording are performed to examine the relaxation to the resting state.

Data Analysis

Data are analyzed and reported as normalized ratios ofbackground-subtracted emission intensities measured in the 460 nm and580 nm channels. Background intensities are then subtracted from eachassay channel. Background intensities are obtained by measuring theemission intensities during the same time periods from identicallytreated assay wells in which there are no cells. The response as afunction of time is then reported as the ratios obtained using thefollowing formula:

${R(t)} = \frac{\left( {{intensity}_{460\mspace{11mu} {nm}} - {background}_{460\mspace{11mu} {nm}}} \right)}{\left( {{intensity}_{580\mspace{11mu} {nm}} - {background}_{580\mspace{11mu} {nm}}} \right)}$

The data is further reduced by calculating the initial (R_(i)) and final(R_(f)) ratios. These are the average ratio values during part or all ofthe pre-stimulation period, and during sample points during thestimulation period. The response to the stimulus

R=R_(f)/R_(i) is then calculated.

Control responses are obtained by performing assays in the presence of acompound with the desired properties (positive control), such astetracaine, and in the absence of pharmacological agents (negativecontrol). Responses to the negative (N) and positive (P) controls arecalculated as above. The compound antagonist activity A is defined as:

$A = {\frac{R - P}{N - P}*100.}$

where R is the ratio response of the test compound.

Electrophysiology Assays for NaV Activity and Inhibition of TestCompounds

Patch clamp electrophysiology was used to assess the efficacy andselectivity of sodium channel blockers in dorsal root ganglion neurons.Rat neurons were isolated from the dorsal root ganglions and maintainedin culture for 2 to 10 days in the presence of NGF (50 ng/ml) (culturemedia consisted of NeurobasalA supplemented with B27, glutamine andantibiotics). Small diameter neurons (nociceptors, 8-12 μm in diameter)have been visually identified and probed with fine tip glass electrodesconnected to an amplifier (Axon Instruments). The “voltage clamp” modehas been used to assess the compound's IC50 holding the cells at −60 mV.In addition, the “current clamp” mode has been employed to test theefficacy of the compounds in blocking action potential generation inresponse to current injections. The results of these experiments havecontributed to the definition of the efficacy profile of the compounds.

Voltage-Clamp Assay in DRG Neurons

TTX-resistant sodium currents were recorded from DRG somata using thewhole-cell variation of the patch clamp technique. Recordings were madeat room temperature (˜22° C.) with thick walled borosilicate glasselectrodes (WPI; resistance 3-4 M

using an Axopatch 200B amplifier (Axon Instruments). After establishingthe whole-cell configuration, approximately 15 minutes were allowed forthe pipette solution to equilibrate within the cell before beginningrecording. Currents were lowpass filtered between 2-5 kHz and digitallysampled at 10 kHz. Series resistance was compensated 60-70% and wasmonitored continuously throughout the experiment. The liquid junctionpotential (−7 mV) between the intracellular pipette solution and theexternal recording solution was not accounted for in the data analysis.Test solutions were applied to the cells with a gravity driven fastperfusion system (SF-77; Warner Instruments).

Dose-response relationships were determined in voltage clamp mode byrepeatedly depolarizing the cell from the experiment specific holdingpotential to a test potential of +10 mV once every 60 seconds. Blockingeffects were allowed to plateau before proceeding to the next testconcentration.

Solutions

Intracellular solution (in mM): Cs—F (130), NaCl (10), MgCl₂ (1), EGTA(1.5), CaCl2 (0.1), HEPES (10), glucose (2), pH=7.42, 290 mOsm.

Extracellular solution (in mM): NaCl (138), CaCl₂ (1.26), KCl (5.33),KH₂PO₄ (0.44), MgCl₂ (0.5), MgSO₄ (0.41), NaHCO₃ (4), Na₂HPO₄ (0.3),glucose (5.6), HEPES (10), CdCl₂ (0.4), NiCl₂ (0.1), TTX (0.25×10⁻³).

Current-Clamp Assay for NaV Channel Inhibition Activity of Compounds

Cells were current-clamped in whole-cell configuration with a Multiplamp700A amplifier (Axon Inst). Borosilicate pipettes (4-5 Mohm) were filledwith (in mM): 150 K-gluconate, 10 NaCl, 0.1 EGTA, 10 Hepes, 2 MgCl₂,(buffered to pH 7.34 with KOH). Cells were bathed in (in mM): 140 NaCl,3 KCl, 1 MgCl₂, 1 CaCl₂, and 10 Hepes). Pipette potential was zeroedbefore seal formation; liquid junction potentials were not correctedduring acquisition. Recordings were made at room temperature.

The exemplified compounds of Table 2 herein are active against one ormore sodium channels as measured using the assays described hereinaboveas presented in Table 4.

TABLE 4 IC50/EC50 Bins: +++ <= 0.5 < ++ <= 5.0 < + PercentActivityBins: + <= 25.0 < ++ <= 100.0 < +++ Cmpd. No. Binned IC50 1 +++ 2 +++

Many modifications and variations of the embodiments described hereinmay be made without departing from the scope, as is apparent to thoseskilled in the art. The specific embodiments described herein areoffered by way of example only.

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein: ring Z is athiazole or thiadiazole optionally substituted with 0 to 2 occurrencesof R; and R, R₁, R₂, R₃, and R₄ are hydrogen, C1-C6 aliphatic, aryl,C3-C8 cycloaliphatic, halo, CN, NO₂, CF₃, OCF₃, OH, NH₂, NH(C1-C6aliphatic), N(C1-C6 aliphatic)₂, COOH, COO(C1-C6 aliphatic), O(C1-C6aliphatic), CHF₂, or CH₂F.
 2. The compound of claim 1, wherein Z is

or


3. The compound of claim 1, wherein Z is


4. The compound of claim 1, wherein R₁, R₂, R₃, and R₄ are hydrogen,halo, or CF₃.
 5. The compound of claim 1, wherein Z is

and R₁, R₂, R₃, and R₄ are hydrogen, halo, or CF₃.
 6. The compound ofclaim 1, wherein R₁, R₂, R₃, and R₄ are halo or hydrogen.
 7. Thecompound of claim 1, wherein R₂ and R₃ are Cl.
 8. The compound of claim1, wherein at least one of R₁, R₂, R₃, or R₄ is CF₃.
 9. The compound ofclaim 1, wherein R₁, R₂, R₃, and R₄ are CF₃ or H.
 10. The compound ofclaim 1, wherein R₂ is CF₃.
 11. A compound of formula IA:

or a pharmaceutically acceptable salt thereof, wherein: ring Z is athiazole or thiadiazole optionally substituted with 0 to 2 occurrencesof R; and R, R₁, R₂, R₃, and R₄ are hydrogen, C1-C6 aliphatic, aryl,C3-C8 cycloaliphatic, halo, CN, NO₂, CF₃, OCF₃, OH, NH₂, NH(C1-C6aliphatic), N(C1-C6 aliphatic)₂, COOH, COO(C1-C6 aliphatic), O(C1-C6aliphatic), CHF₂, or CH₂F.
 12. The compound of claim 11, wherein Z is anoptionally substituted ring selected from:


13. The compound of claim 11, wherein Z is


14. The compound of claim 11, wherein R₁, R₂, R₃, and R₄ are hydrogen,C1-C6 aliphatic, halo, or CF₃.
 15. The compound of claim 11, wherein Zis

and R₁, R₂, R₃, and R₄ are hydrogen, C1-C6 aliphatic, halo, or CF₃. 16.The compound of claim 11, wherein R₁, R₂, R₃, and R₄ are hydrogen orhalo.
 17. The compound of claim 11, wherein R₁, R₂, R₃, and R₄ are H orCl.
 18. The compound of claim 11, wherein R₂ and R₃ are Cl.
 19. Thecompound of claim 11, wherein at least one of R₁, R₂, R₃, or R₄ is CF₃.20. The compound of claim 11, wherein R₁, R₂, R₃, and R₄ are hydrogen orCF₃.
 21. The compound of claim 11, wherein R₂ is CF₃.
 22. The compoundof claim 11 selected from the group consisting of


23. A pharmaceutical composition comprising a compound of claim 1 and apharmaceutically acceptable carrier.
 24. A method of treating orlessening the severity in a subject of acute, chronic, neuropathic, orinflammatory pain, arthritis, migraine, cluster headaches, trigeminalneuralgia, herpetic neuralgia, general neuralgias, epilepsy or epilepsyconditions, neurodegenerative disorders, psychiatric disorders such asanxiety and depression, dipolar disorder, myotonia, arrhythmia, movementdisorders, neuroendocrine disorders, ataxia, multiple sclerosis,irritable bowel syndrome, incontinence, visceral pain, osteoarthritispain, postherpetic neuralgia, diabetic neuropathy, radicular pain,sciatica, back pain, head or neck pain, severe or intractable pain,nociceptive pain, breakthrough pain, postsurgical pain, cancer pain,stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateralsclerosis, stress- or exercise induced angina, palpitations,hypertension, migraine, or abormal gastro-intestinal motility,comprising administering an effective amount of a compound according toclaim 1, or a pharmaceutically acceptable composition comprising acompound to said subject in need thereof.
 25. The method according toclaim 24, wherein said method is used for treating or lessening theseverity of femur cancer pain; non-malignant chronic bone pain;rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic lowback pain; neuropathic low back pain; myofascial pain syndrome;fibromyalgia; temporomandibular joint pain; chronic visceral pain,including, abdominal; pancreatic; IBS pain; chronic and acute headachepain; migraine; tension headache, including, cluster headaches; chronicand acute neuropathic pain, including, post-herpetic neuralgia; diabeticneuropathy; HIV-associated neuropathy; trigeminal neuralgia;Charcot-Marie Tooth neuropathy; hereditary sensory neuropathies;peripheral nerve injury; painful neuromas; ectopic proximal and distaldischarges; radiculopathy; chemotherapy induced neuropathic pain;radiotherapy-induced neuropathic pain; post-mastectomy pain; centralpain; spinal cord injury pain; post-stroke pain; thalamic pain; complexregional pain syndrome; phantom pain; intractable pain; acute pain,acute post-operative pain; acute musculoskeletal pain; joint pain;mechanical low back pain; neck pain; tendonitis; injury/exercise pain;acute visceral pain, including, abdominal pain; pyelonephritis;appendicitis; cholecystitis; intestinal obstruction; hernias; etc; chestpain, including, cardiac pain; pelvic pain, renal colic pain, acuteobstetric pain, including, labor pain; cesarean section pain; acuteinflammatory, burn and trauma pain; acute intermittent pain, including,endometriosis; acute herpes zoster pain; sickle cell anemia; acutepancreatitis; breakthrough pain; orofacial pain including sinusitispain, dental pain; multiple sclerosis (MS) pain; pain in depression;leprosy pain; Behcet's disease pain; adiposis dolorosa; phlebitic pain;Guillain-Barre pain; painful legs and moving toes; Haglund syndrome;erythromelalgia pain; Fabry's disease pain; bladder and urogenitaldisease, including, urinary incontinence; hyperactivity bladder; painfulbladder syndrome; interstitial cyctitis (IC); or prostatitis; complexregional pain syndrome (CRPS), type I and type II; or angina-inducedpain.